Nerve stimulation methods for averting imminent onset or episode of a disease

ABSTRACT

Transcutaneous electrical and magnetic nerve stimulation devices are disclosed, along with methods of averting imminent medical attacks using energy that is delivered noninvasively by the devices. The attacks comprise asthma attack, epileptic seizure, attacks of migraine headache, transient ischemic attack or stroke, onset of atrial fibrillation, myocardial infarction, onset of ventricular fibrillation or tachycardia, panic attack, and attacks of acute depression. The imminence of an attack is forecasted using grey-box or black-box models as used in control theory. In preferred embodiments of the disclosed methods, a vagus nerve in the neck of a patient is stimulated noninvasively to avert the attack.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of patent application Ser. No.13/357,010, entitled NERVE STIMULATION METHODS FOR AVERTING IMMINENTONSET OR EPISODE OF A DISEASE, to SIMON et al., with a filing date ofJan. 24, 2012, which claims the benefit of priority to U.S. ProvisionalPatent Application No. 61/552,217 filed Oct. 27, 2011 and is acontinuation-in-part of U.S. patent application Ser. No. 13/279,437filed Oct. 24, 2011 which is a continuation-in-part of U.S. patentapplication Ser. No. 13/222,087 filed Aug. 31, 2011, which is acontinuation-in-part of U.S. patent application Ser. No. 13/183,765filed Jul. 15, 2011 which claims the benefit of priority of U.S.Provisional Patent Application No. 61/488,208 filed May 20, 2011 and isa continuation-in-part to U.S. patent application Ser. No. 13/183,721filed Jul. 15, 2011, which claims the benefit of priority of U.S.Provisional Patent Application No. 61/487,439 filed May 18, 2011 and isa continuation-in-part of U.S. patent application Ser. No. 13/109,250filed May 17, 2011, which claims the benefit of priority of U.S.Provisional Patent Application No. 61/471,405 filed Apr. 4, 2011 and isa continuation-in-part of U.S. patent application Ser. No. 13/075,746filed Mar. 30, 2011, which claims the benefit of priority of U.S.provisional patent application 61/451,259 filed Mar. 10, 2011 and is acontinuation-in-part of U.S. patent application Ser. No. 13/005,005filed Jan. 12, 2011, which is a continuation-in-part of U.S. patentapplication Ser. No. 12/964,050 filed Dec. 9, 2010, which claims thebenefit of priority of U.S. Provisional Patent Application No.61/415,469 filed Nov. 19, 2010 and is a continuation-in-part of U.S.patent application Ser. No. 12/859,568 filed Aug. 9, 2010, which is acontinuation-in-part of U.S. patent application Ser. No. 12/408,131filed Mar. 20, 2009 and a continuation-in-part application of U.S.patent application Ser. No. 12/612,177 filed Nov. 9, 2009 now U.S. Pat.No. 8,041,428 issued Oct. 18, 2011 the entire disclosures of which arehereby incorporated by reference.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for prophylactic purposes. Itrelates more specifically to the use of non-invasive devices and methodsfor transcutaneous electrical nerve stimulation and magnetic nervestimulation, which are used in conjunction with methods for forecastingimminent medical disorders, wherein energy that is delivered by suchdevices averts the imminent disorder. The disorders comprise thefollowing medical conditions: asthma attacks, epileptic seizures,migraine or other headaches having sudden onset, ventricularfibrillation/tachycardia, myocardial infarction, transient ischemicattacks or strokes, atrial fibrillation, panic attacks and attacks ofdepression. According to the invention, a patient at risk for such anattack is monitored, preferably using ambulatory or noninvasive sensors;signals from the sensors are analyzed automatically using a device toforecast that an attack may be imminent; the analyzing device warns thepatient or health provider that an attack may be imminent, or the deviceacts autonomously; and transcutaneous electrical nerve stimulation ormagnetic nerve stimulation, preferably of a vagus nerve, is performed isorder to avert, prevent, delay, abort, shorten, or ameliorate theattack.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue holds significant promise for the treatment ofmany ailments, because such stimulation is generally a wholly reversibleand non-destructive treatment.

One of the most successful applications of modern understanding of theelectrophysiological relationship between muscle and nerves is thecardiac pacemaker. Although origins of the cardiac pacemaker extend backinto the 1800's, it was not until 1950 that the first practical, albeitexternal and bulky, pacemaker was developed. The first truly functional,wearable pacemaker appeared in 1957, and in 1960, the first fullyimplantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to DENO, et al., the disclosure of which is incorporatedherein by reference).

Another application of electrical stimulation of nerves has been thetreatment of radiating pain in the lower extremities by stimulating thesacral nerve roots at the bottom of the spinal cord (see U.S. Pat. No.6,871,099 to WHITEHURST, et al., the disclosure of which is incorporatedherein by reference).

Many such therapeutic applications of electrical stimulation involve thesurgical implantation of electrodes within a patient. In contrast,devices used for the medical procedures that are disclosed herestimulate nerves by transmitting energy to nerves and tissuenon-invasively. Therefore, they may offer the patient an alternativethat does not involve surgery. A medical procedure is defined as beingnon-invasive when no break in the skin (or other surface of the body,such as a wound bed) is created through use of the method, and whenthere is no contact with an internal body cavity beyond a body orifice(e.g., beyond the mouth or beyond the external auditory meatus of theear). Such non-invasive procedures are distinguished from invasiveprocedures (including minimally invasive procedures) in that invasiveprocedures do involve inserting a substance or device into or throughthe skin or into an internal body cavity beyond a body orifice. Forexample, transcutaneous electrical nerve stimulation (TENS) isnon-invasive because it involves attaching electrodes to the surface ofthe skin (or using a form-fitting conductive garment) without breakingthe skin. In contrast, percutaneous electrical stimulation of a nerve isminimally invasive because it involves the introduction of an electrodeunder the skin, via needle-puncture of the skin (see commonly assignedco-pending US Patent Application 2010/0241188, entitled PercutaneousElectrical Treatment of Tissue to ERRICO et al, which is herebyincorporated by reference in its entirety).

Potential advantages of non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures generally present fewer problems withbiocompatibility. In cases involving the attachment of electrodes,non-invasive methods have less of a tendency for breakage of leads, andthe electrodes can be easily repositioned if necessary. Non-invasivemethods are sometimes painless or only minimally painful and may beperformed without the need for even local anesthesia. Less training maybe required for use of non-invasive procedures by medical professionals.In view of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace, and the cost of non-invasive procedures may be reducedrelative to comparable invasive procedures.

Non-invasive transcutaneous electrical nerve stimulation (TENS)electrodes were developed originally for treating different types ofpain, including pain in a joint or lower back, cancer pain,post-operative pain, post-traumatic pain, and pain associated with laborand delivery. As TENS was being developed to treat pain, non-invasiveelectrical stimulation using surface electrodes was simultaneouslydeveloped for additional therapeutic or diagnostic purposes, which areknown collectively as electrotherapy. Neuromuscular electricalstimulation (NMES) stimulates normally innervated muscle in an effort toaugment strength and endurance of normal (e.g., athletic) or damaged(e.g., spastic) muscle. Functional electrical stimulation (FES) is usedto activate nerves innervating muscle affected by paralysis resultingfrom spinal cord injury, head injury, stroke and other neurologicaldisorders, or muscle affected by foot drop and gait disorders. FES isalso used to stimulate muscle as an orthotic substitute, e.g., replace abrace or support in scoliosis management. Another application of surfaceelectrical stimulation is chest-to-back stimulation of tissue, such asemergency defibrillation and cardiac pacing. Surface electricalstimulation has also been used to repair tissue, by increasingcirculation through vasodilation, by controlling edema, by healingwounds, and by inducing bone growth. Surface electrical stimulation isalso used for iontophoresis, in which electrical currents driveelectrically charged drugs or other ions into the skin, usually to treatinflammation and pain, arthritis, wounds or scars.

Stimulation with surface electrodes is also used to evoke a response fordiagnostic purposes, for example in peripheral nerve stimulation (PNS)that evaluates the ability of motor and sensory nerves to conduct andproduce reflexes. Surface electrical stimulation is also used inelectroconvulsive therapy to treat psychiatric disorders; inelectroanesthesia, for example, to prevent pain from dental procedures;and in electrotactile speech processing to convert sound into tactilesensation for the hearing impaired. All of the above-mentionedapplications of surface electrode stimulation are intended not to damagethe patient, but if higher currents are used with special electrodes,electrosurgery may be performed as a means to cut, coagulate, desiccate,or fulgurate tissue [Mark R. PRAUSNITZ. The effects of electric currentapplied to skin: A review for transdermal drug delivery. Advanced DrugDelivery Reviews 18 (1996) 395-425].

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation is non-invasivebecause the magnetic field is produced by passing a time-varying currentthrough a coil positioned outside the body, inducing at a distance anelectric field and electric current within electrically-conductingbodily tissue. The electrical circuits for magnetic stimulators aregenerally complex and expensive and use a high current impulse generatorthat may produce discharge currents of 5,000 amps or more, which ispassed through the stimulator coil to produce a magnetic pulse. Theprinciples of electrical nerve stimulation using a magnetic stimulator,along with descriptions of medical applications of magnetic stimulation,are reviewed in: Chris HOVEY and Reza Jalinous, The Guide to MagneticStimulation, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006.

Despite its attractiveness, non-invasive electrical stimulation of anerve is not always possible or practical. This is primarily because thestimulators may not be able to stimulate a deep nerve selectively orwithout producing excessive pain, because the stimulation mayunintentionally stimulate nerves other than the nerve of interest,including nerves that cause pain. For this reason, forms of electricalstimulation other than TENS may be best suited for the treatment ofparticular types of pain [Paul F. WHITE, Shitong Li and Jen W. Chiu.Electroanalgesia: Its Role in Acute and Chronic Pain Management. AnesthAnalg 92(2001):505-13]. Consequently, there remains a long-felt butunsolved need to stimulate nerves totally non-invasively, selectively,and essentially without producing pain.

As compared with what would be experienced by a patient undergoingnon-invasive stimulation with conventional TENS or magnetic stimulationmethods, the stimulators disclosed herein and in the relatedapplications cited in the section CROSS REFERENCE TO RELATEDAPPLICATIONS produce relatively little pain for a given depth ofstimulus penetration, but nevertheless stimulate the target nerve toachieve therapeutic results. Or conversely, for a given amount of painor discomfort on the part of the patient (e.g., the threshold at whichsuch discomfort or pain begins), the stimulators disclosed herein and inthe related applications achieve a greater depth of penetration or powerof the stimulus under the skin. When some nerves are stimulatedelectrically, they may produce undesirable responses in addition to thetherapeutic effect that is intended. For example, the stimulated nervesmay produce unwanted muscle twitches. The stimulators disclosed hereinand in the related applications may selectively produce only theintended therapeutic effect, when they are used to stimulate the targetnerve.

The stimulators disclosed herein are particularly useful for performingnoninvasive stimulation of a vagus nerve in the neck. Invasive vagusnerve stimulation (VNS, also known as vagal nerve stimulation) wasdeveloped initially for the treatment of partial onset epilepsy and wassubsequently developed for the treatment of depression and otherdisorders. The left vagus nerve is ordinarily stimulated at a locationwithin the neck by first surgically implanting an electrode there, thenconnecting the electrode to an electrical stimulator [Patent numbersU.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis, to ZABARA;U.S. 6,341,236 entitled Vagal nerve stimulation techniques for treatmentof epileptic seizures, to OSORIO et al and U.S. Pat. No. 5,299,569entitled Treatment of neuropsychiatric disorders by nerve stimulation,to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas.Deep brain stimulation, vagal nerve stimulation and transcranialstimulation: An overview of stimulation parameters and neurotransmitterrelease. Neuroscience and Biobehavioral Reviews 33 (2009) 1042-1060;GROVES D A, Brown V. J. Vagal nerve stimulation: a review of itsapplications and potential mechanisms that mediate its clinical effects.Neurosci Biobehav Rev (2005) 29:493-500; Reese TERRY, Jr. Vagus nervestimulation: a proven therapy for treatment of epilepsy strives toimprove efficacy and expand applications. Conf Proc IEEE Eng Med BiolSoc. 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation:current concepts. Neurosurg Focus 25 (3,2008):E9, pp. 1-4]. An advantageof devices according to the present invention is that they can be usedto perform VNS noninvasively on the neck without causing pain ornonselective nerve stimulation.

Vagus nerve stimulation has heretofore been used to treat patients whoare only at a statistical risk for experiencing epileptic seizures. Forexample, the patient will have been diagnosed with epilepsy or isotherwise considered to be at risk for having seizures, usingstatistical or epidemiological risk assessment methods. Such riskassessment methods predict only the probability of a seizure over aperiod of typically weeks or months, but do not attempt to forecast thatan attack is imminent within a matter of minutes or other short periodof time. Thus, currently practiced VNS treatment methods stimulate thepatient chronically or at scheduled times, rather than stimulatingprophylactically based on the likely onset of predicted epilepticseizures.

It would be preferable to actually forecast an epileptic seizure so asto perform a prophylactic countermeasure, and methods have been proposedto do so [MORMANN F, Andrzejak R G, Elger C E, Lehnertz K. Seizureprediction: the long and winding road. Brain 130(Pt 2,2007):314-33].Proposed countermeasures are the on-demand excretion of fast-actinganticonvulsant substances, local cooling, biofeedback operantconditioning, and electrical or other stimulation to reset braindynamics to a state that will not develop into a seizure. The electricalstimulation countermeasures that have been proposed involved deep-brainstimulation or other uses of implanted electrodes, but not non-invasivevagal nerve stimulation. In one aspect of the present invention,non-invasive vagal nerve stimulation is performed as a countermeasurefor a forecasted epileptic seizure, instead of using implantedelectrodes or brain stimulation.

For acute events other than epileptic seizures, the literature on “acuterisk factors” does not attempt to forecast and take prophylactic nervestimulation countermeasures against the imminent disease event. Instead,the goal has been detection of the attack in its early stages (e.g.,transient ischemia, thrombosis, and initial signs of ventricularfibrillation, in the case of cardiovascular events [TOFLER G H, Muller JE. Triggering of acute cardiovascular disease and potential preventivestrategies. Circulation. 114(17, 2006):1863-72]).The treatment methodsthat are currently practiced in connection with such acute events aretherefore generally intended only to lessen the probability that anacute event will occur over a period of weeks or months, or possibly toabort an attack that is already in progress, but not to predict andavert an attack is that is imminent within a matter of minutes or othershort period of time. In one aspect of the present invention, suchnear-term forecasting, along with non-invasive vagal nerve stimulation,is performed as a countermeasure for many types of acute events,comprising: asthma attacks, epileptic seizures, migraine or otherheadaches having sudden onset, ventricular fibrillation/tachycardia,myocardial infarction, transient ischemic attacks or strokes, atrialfibrillation, panic attacks or attacks of depression. Thus, the presentinvention differs from the prior art in that it attempts to forecastsuch an imminent attack (generally within seconds to hours) and warnthat an attack may be imminent, then use noninvasive nerve stimulationto prevent or avert the attack.

The forecast that an attack may be imminent is based upon the automaticanalysis of physiological and/or environmental signals that are providedpreferably by non-invasive sensors situated on, about, or near thepatient. The simultaneity of data provided by multiple sensors may bemore informative for purpose of forecasting than data provided by thesensors considered individually, i.e. correlations between the values ofdifferent physiological and/or environmental variables may be assignificant as the values of the variables themselves. Such sensors maycomprise those used in Holter and bedside monitoring applications, formonitoring heart rate and heart rate variability, ECG and arrhythmias,EEG and sleep state, brain function, respiration, capnometry and breathanalysis, core temperature, hydration and blood volume, blood pressureand flow, oxygenation, EMG, motion and posture, gait, skin conductanceand skin temperature. The sensors may also be embedded in garments orplaced in sports wristwatches, for example, as currently used inprograms that monitor the physiological status of soldiers and patients[G. A. Shaw, A. M. Siegel, G. Zogbi, and T. P. Opar. Warfighterphysiological and environmental monitoring: a study for the U.S. ArmyResearch Institute in Environmental Medicine and the Soldier SystemsCenter. MIT Lincoln Laboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141;Tuba YILMAZ, Robert Foster and Yang Hao. Detecting Vital Signs withWearableWireless Sensors. Sensors 10(2010), 10837-10862; Shyamal PATEL,Hyung Park, Paolo Bonato, Leighton Chan and Mary Rodgers. A review ofwearable sensors and systems with application in rehabilitation. Journalof NeuroEngineering and Rehabilitation 2012, 9:21, pp. 1-17; RobertMATTHEWS, Neil J. McDonald, Leonard J. Trejo. Psycho-physiologicalsensor techniques: An overview. 11th International Conference on HumanComputer Interaction (HCII), Las Vegas, Nev., Jul. 22-27, 2005. pp.1-10]. More sophisticated versions of conventional ambulatory monitoringdevices may also be used, for example, when electrical impedancemeasurements are used noninvasively to image the lung, heart, or brain[David Holder. Electrical impedance tomography: methods, history, andapplications. Institute of Physics Publishing, Bristol and Philadelphia,2005].

Sensors may be selected according to their relevance to the physiologyof the disease that is being forecast. For example, for someapplications the sensors may measure bodily chemicals using non-invasivetransdermal reverse iontophoresis [LEBOULANGER B, Guy R H,Delgado-Charro M B. Reverse iontophoresis for non-invasive transdermalmonitoring. Physiol Meas. 25(3,2004):R35-50]. As an example, internalchemical levels that may be relevant to the pathophysiology of amigraine attack and that may be measured by transdermal reverseiontophoresis comprise potassium, glutamate, stress hormones (e.g., ACTHand/or cortisol), and glucose.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[Casson A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3,2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst34(2010):195-212].

Noninvasive sensors that provide an indication of the state of thepatient's central nervous system may also be applied at sites of thebody other than the head. For example, electrodermal measurements, alsoknown as galvanic skin responses, have been used traditionally inpsychophysiology to indicate the patient's emotional and/or cognitivestate. Ordinarily, such measurement is made on the palm, volar side of afinger, or feet of a patient, although electrodermal measurement atother sites such as the shoulder may be useful as well [Marieke vanDOOREN, J. J. G. (Gert-Jan) de Vries, Joris H. Janssen. Emotionalsweating across the body: Comparing 16 different skin conductancemeasurement locations. Physiology & Behavior 106(2012): 298-304]. Since1981, a particular skin conductance method has been the internationalstandard technique to record and analyze electrodermal activity (EDA)[Wolfram BOUCSEIN. Electrodermal activity, 2nd Ed., New York: Springer,2012, pp. 1-618]. Both short-term electrodermal responses to stimuli andlonger term unprovoked electrodermal activity levels are measured.Recently, miniature electrodermal sensors have become available for usein ambulatory monitoring. Data that they produce have been shown tocorrelate with the onset of epileptic seizures, especially when used inconjunction with an accelerometer [Ming-Zher POH, Nicholas C. Swenson,and Rosalind W. Picard. A wearable sensor for unobtrusive, long-termassessment of electrodermal activity. IEEE Transactions on BiomedicalEngineering 57(5,2010):1243-1252; Ming-Zher POH, Tobias Loddenkemper,Nicholas C. Swenson, Shubhi Goyal, Joseph R. Madsen and Rosalind W.Picard. Continuous monitoring of electrodermal activity during epilepticseizures using a wearable sensor. 32nd Annual International Conferenceof the IEEE EMBS, Buenos Aires, Argentina, Aug. 31-Sep. 4, 2010, pp.4415-4418; Ming-Zher POH, Tobias Loddenkemper, Claus Reinsberger,Nicholas C. Swenson, Shubhi Goyal, Mangwe C. Sabtala, Joseph R. Madsen,and Rosalind W. Picard. Convulsive seizure detection using a wrist-wornelectrodermal activity and accelerometry biosensor. Epilepsia53(5,2012):e93-e97].

Electrodermal activity is due to sweat that is secreted by eccrine sweatglands and excreted through sweat ducts. Secretion by sweat glands isunder the control of sympathetic nerves, and consequently, EDA serves asa surrogate of the activity of the sympathetic nervous system, asinfluenced by central nervous system components [Wolfram BOUCSEIN.Electrodermal activity, 2nd Ed., New York: Springer, 2012, pp. 1-618;Hugo D. CRITCHLEY. Electrodermal responses: what happens in the brain.Neuroscientist 8(2,2002):132-142; Michael E. DAWSON, Anne M. Schell andDiane L. Filion. The electrodermal system. In: John T. Cacioppo, LouisG. Tassinary and Gary G. Berntson, eds. Handbook of Psychophysiology,2nd. Ed., Cambridge, UK: Cambridge University press, 2000, Chapter 8,pp. 200-223; FREDRIKSON M, Furmark T, Olsson M T, Fischer H, AnderssonJ, L{dot over (a)}ngstrom B. Functional neuroanatomical correlates ofelectrodermal activity: a positron emission tomographic study.Psychophysiology 35(2,1998):179-85; Henrique SEQUEIRA, Pascal Hot,Laetitia Silvert, Sylvain Delplanque. Electrical autonomic correlates ofemotion. International Journal of Psychophysiology 71 (2009): 50-56].

Several non-invasive measurements other than electrodermal activity canalso be used to assess sympathetic activity in a patient, and they mayprovide an indication of parasympathetic activity as well [MENDES, W. B.Assessing the autonomic nervous system. Chapter 7 In: E. Harmon-Jonesand J. Beer (Eds.) Methods in Social Neuroscience. New York: GuilfordPress, 2009, pp. 118-147]. One such measurement involves heart ratevariability, which may be understood from the fact that both heart rateand electrodermal activity are controlled in part by neural pathwaysinvolving, for example, the anterior cingulate cortex [Hugo D.CRITCHLEY, Christopher J. Mathias, Oliver Josephs, et al. Humancingulate cortex and autonomic control: converging neuroimaging andclinical evidence. Brain 126(2003):2139-2152; Hugo D. CRITCHLEY.Electrodermal responses: what happens in the brain. Neuroscientist8(2,2002):132-142]. Heart rate variability is conventionally assessed byexamining the Fourier spectrum of successive heart rate intervals thatare extracted from an electrocardiogram (RR-intervals). Typically, ahigh-frequency respiratory component (0.15 to 0.4 Hz, centered aroundabout 0.25 Hz, and varying with respiration) and a slower, low frequencycomponent (from about 0.04 to 0.13 Hz) due primarily tobaroreceptor-mediated regulation of blood pressure related to Mayerwaves, are found in the power spectrum of the heart rate. Even slowerrhythms (<0.04 Hz), thought to reflect temperature, blood volume,renin-angiotensin regulation, as well as circadian rhythms, may also bepresent. The high frequency respiratory component is primarily mediatedby vagal activity, and consequently, high frequency spectral power isoften used as an index of cardiac parasympathetic tone. Low-frequencypower can be a valid indicator of cardiac sympathetic activity undercertain conditions, with the understanding that baroreceptor regulationof blood pressure can be achieved through both sympathetic andparasympathetic pathways. However, more elaborate indices of sympatheticand parasympathetic activity may also be extracted from the variation insuccessive heart rate intervals [U. Rajendra ACHARYA, K. Paul Joseph, N.Kannathal, Choo Min Lim and Jasjit S. Suri. Heart rate variability: areview. Medical and Biological Engineering and Computing 44(12,2006),1031-1051]. Considering that neither electrodermal nor heart ratevariability indices of sympathetic activity unambiguously characterizesympathetic activity within the central nervous system, it is preferredthat they both be measured. In fact, additional noninvasive measures ofsympathetic activity, such as variability of QT intervals, arepreferably measured as well [BOETTGER S, Puta C, Yeragani V K, Donath L,Muller H J, Gabriel H H, Bar K J. Heart rate variability, QTvariability, and electrodermal activity during exercise. Med Sci SportsExerc 42(3,2010):443-448].

The ambulatory sensors may also comprise accelerometers for detailedmeasurement of the patients' posture, movements andmetabolically-relevant activity [Mathie M J, Coster A C, Lovell N H,Celler B G. Accelerometry: providing an integrated, practical method forlong-term, ambulatory monitoring of human movement. Physiol Meas. 2004April; 25(2):R1-20] or for evaluation of potential motion artifacts insignals such as the EEG [Sweeney K T, Leamy D J, Ward T E, McLoone S.Intelligent artifact classification for ambulatory physiologicalsignals. Conf Proc IEEE Eng Med Biol Soc. 2010:6349-6352].

It is understood that acute attacks may also be influenced by thepatient's environment, not only for respiratory attacks, but for othertypes of attacks as well [Annette PETERS, Douglas W. Dockery, James E.Muller, Murray A. Mittleman. Increased Particulate Air Pollution and theTriggering of Myocardial Infarction. Circulation 103(2001): 2810-2815].Therefore, nearby sensors for environmental variables may also be usefulfor making forecasts, the values of which may be transmitted, directlyin the case of ambulatory monitors or wirelessly in the case ofnon-portable sensors, to the device that is aggregating the signals usedto make the forecast. For example, vest-based sensors would be usefulfor the evaluation of potential environmental asthma triggers [e.g.,Kirk J. Englehardt and John Toon. Asthma attack: Vest-based sensorsmonitor environmental exposure to help understand causes: web page (www)at the Georgia Tech Research Institute (.gtri) of Georgia Tech (.gatech)educational domain (.edu) in subdomain:/casestudy/asthma-vest-helps-id-asthma-causes; patent applicationUS20110144515, entitled Systems and methods for providing environmentalmonitoring, to Bayer et al.; and patent U.S. Pat. No. 7,119,900,entitled Pollen sensor and method, to Okumura et al]. In the presentinvention, an environmental sensors may monitor triggering factorscomprising one or more of: formaldehyde, carbon monoxide, carbondioxide, ozone, a nitrogen oxide, a sulfur oxide, total volatile organiccompounds, ammonia, airborne particles or dust, pollen, mold, animaldander, dust mites, smoke particulates, ambient temperature, ambienthumidity, ambient light, ambient sound, or other environmental factorsto which the patient may be sensitive.

A common feature of asthma attacks, epileptic seizures, migraine orother headaches having sudden onset, ventricularfibrillation/tachycardia, myocardial infarction, transient ischemicattacks or strokes, atrial fibrillation, panic attacks, attacks ofdepression, and the like, is that they all may occur suddenly. On onelevel, they all have different particular mechanisms, but on a moregeneral level they all appear to be types of phase transitions, whereinthere is an abrupt change from a possibly normal physiological dynamicphase to a pathological dynamical phase. As a type of phase transition,they share features with non-biological, non-equilibrium phasetransitions such as the onset of lasing in a laser or the abrupt changefrom laminar to turbulent flow in fluid dynamics. Such phase transitionsare described by non-linear dynamical equations that exhibit genericproperties immediately before the change of phase occurs [Scheffer M,Bascompte J, Brock W A, Brovkin V, Carpenter S R, Dakos V, Held H, vanNes E H, Rietkerk M, Sugihara G. Early-warning signals for criticaltransitions. Nature 461(7260,2009):53-9; Christian Kuehn. A mathematicalframework for critical transitions: normal forms, variance andapplications. arXiv:1101.2908v1 math.DS]. Therefore, it may be generallypossible to predict the imminence of pathological phase transitions,such as the pathological attacks indicated above, using nonlinear aswell as ad hoc analyses of relevant noninvasive ambulatory signals thatare obtained using ambulatory sensors, such as those described in theprevious paragraphs.

For many pathological attacks or transitions, it is thought that vagalnerve stimulation is protective. Therefore, a patient who is promptlyforewarned by the invention that such a pathological dynamical event isimminent may use noninvasive vagus nerve stimulation as a prophylacticcountermeasure, with little risk of pain or adverse consequences, andwith potentially much to gain by averting the onset or episode of thedisease. According to the present invention, the prophylacticstimulation will ordinarily be performed in “open-loop” mode, whereinthe sensors do not provide immediate feedback to determine theparameters of the stimulation (frequency, pulse width, number of pulsesper burst, etc.). However, also according to the present invention,preliminary stimulations may be performed in “closed -loop” mode,wherein the sensors do provide feedback, in order to select thestimulation parameters that will eventually be used during the open-loopprophylactic stimulation. If preliminary parameter selection has not yettaken place, the prophylactic stimulation may also be performed in“closed-loop” feedback mode. Because a goal of the devices is toforecast an imminent event, feedforward methods are generally preferred,whether or not feedback methods are also used. Although the preferredstimulation methods are noninvasive, it is understood that invasivestimulation and data acquisition methods may also be used for a patientin whom electrodes have already been implanted. It is also understoodthat the noninvasive vagal nerve stimulation countermeasure may be usedin conjunction with other countermeasures (e.g., inhaler or EpiPen foran asthma attack).

SUMMARY OF THE INVENTION

Devices and methods are described to produce prophylactic or therapeuticeffects in a patient, by utilizing an energy source that transmitsenergy non-invasively to nervous tissue. In particular, the discloseddevices can transmit energy to, or in close proximity to, a vagus nervein the neck of the patient, in order to temporarily stimulate, blockand/or modulate electrophysiological signals in that nerve. The methodsthat are disclosed herein comprise stimulating a vagus nerve withparticular stimulation waveform parameters, preferably using the nervestimulator devices that are also described herein.

A novel stimulator device is used to modulate electrical activity of avagus nerve or other nerves or tissue. The stimulator comprises a sourceof electrical power and two or more remote electrodes that areconfigured to stimulate a deep nerve relative to the nerve axis. Thedevice also comprises continuous electrically conducting media withwhich the electrodes are in contact. The conducting medium is also incontact with an interface element that makes physical contact with thepatient's skin. The interface element may be electrically insulating(dielectric) material, such as a sheet of Mylar, in which caseelectrical coupling of the device to the patient is capacitive. In otherembodiments, the interface element is electrically conducting material,such as an electrically conducting or permeable membrane, in which caseelectrical coupling of the device to the patient is ohmic. The interfaceelement may have a shape that conforms to the contour of a target bodysurface of a patient when the medium is applied to the target bodysurface. In another embodiment of the invention, a non-invasive magneticstimulator device is used to modulate electrical activity of a vagusnerve or other nerves or tissue, without actually introducing a magneticfield into the patient.

For the present medical applications, the electrode-based device or amagnetic stimulation device is ordinarily applied to the vicinity of thepatient's neck. In one embodiment of the electrode-based invention, thestimulator comprises two electrodes that lie side-by-side withinseparate stimulator heads, wherein the electrodes are separated byelectrically insulating material. Each electrode is in continuouscontact with an electrically conducting medium that extends from theinterface element of the stimulator to the electrode. The interfaceelement also contacts the patient's skin when the device is inoperation. The conducting media for different electrodes are alsoseparated by electrically insulating material.

In another embodiment of the invention, a non-invasive magneticstimulator device is ordinarily applied to the vicinity of the patient'sneck. In a preferred embodiment of the magnetic stimulator, thestimulator comprises two toroidal windings that lie side-by-side withinseparate stimulator heads, wherein the toroidal windings are separatedby electrically insulating material. Each toroid is in continuouscontact with an electrically conducting medium that extends from thepatient's skin to the toroid.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator coil, such that the electrodes or magneticstimulator produce an electric current and/or an electric field withinthe patient. The electrical or magnetic stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to 600 V/m and anelectrical field gradient of greater than 2 V/m/mm.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of 0 to 30 volts. The current is passedthrough the electrodes in bursts of pulses. There may be 1 to 20 pulsesper burst, preferably five pulses. Each pulse within a burst has aduration of 20 to 1000 microseconds, preferably 200 microseconds. Aburst followed by a silent inter-burst interval repeats at 1 to 5000bursts per second (bps), preferably at 15-50 bps. The preferred shape ofeach pulse is a full sinusoidal wave. However, triangular or squareother shapes known in the art may be used as well. The preferredstimulator shapes an elongated electric field of effect that can beoriented parallel to a long nerve, such as a vagus nerve in a patient'sneck. By selecting a suitable waveform to stimulate the nerve, alongwith suitable parameters such as current, voltage, pulse width, pulsesper burst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves thatproduce pain.

The currents passing through the coils of the magnetic stimulator willsaturate its core (e.g., 0.1 to 2 Tesla magnetic field strength forSupermendur core material). This will require approximately 0.5 to 20amperes of current being passed through each coil, typically 2 amperes,with voltages across each coil of 10 to100 volts. The current is passedthrough the coils in bursts of pulses as described above, shaping anelongated electrical field of effect as with the electrode-basedstimulator.

The disclosure teaches methods for the forecasting of an imminentmedical attack and then using the disclosed stimulators to avert theattack. The forecast that an attack may be imminent is based upon theautomatic analysis of physiological and/or environmental signals thatare provided preferably by non-invasive sensors situated on, about, ornear the patient. Such sensors may comprise those used in Holter andbedside monitoring applications, for monitoring heart rate and heartrate variability, ECG, EMG, respiration, core temperature, hydration,blood pressure, brain function, oxygenation, motion and posture, skinconductance and skin temperature. Environmental sensors may also be usedto monitor external triggering factors, comprising one or more of:formaldehyde, carbon monoxide, carbon dioxide, ozone, a nitrogen oxide,a sulfur oxide, total volatile organic compounds, ammonia, airborneparticles or dust, pollen, mold, animal dander, dust mites, smokeparticulates, ambient temperature, ambient humidity, ambient light,ambient sound, or other environmental factors to which the patient maybe sensitive. Teachings of the present invention demonstrate how totreat a patient prophylactically, by positioning the disclosednoninvasive stimulator devices against body surfaces, particularly at alocation in the vicinity of the patient's neck where a vagus nerve islocated under the skin.

The stimulation is performed with a sinusoidal burst waveform asdescribed above, followed by silent inter-burst period repeats itselfwith a period of T. In a preferred embodiment, the sinusoidal period τmay be 200 microseconds; the number of pulses per burst may be N=5; andthe whole pattern of burst followed by silent inter-burst period mayhave a period of T=40000 microseconds, which is comparable to 25 Hzstimulation.

The stimulation is performed typically for 30 minutes, but in someapplications the stimulation may be performed for as little as 30 to 120seconds. Treatment may be performed on the left or right or both vagusnerves, or it may be performed alternately on the left and right vagusnerves. The stimulation may be repeated if the acute medical event hasnot yet been averted.

Forecasting and averting of an acute event may be implemented within thecontext of control theory. In one embodiment, a controller, comprisingthe disclosed vagus nerve stimulator, a PID, and a feedforward model ,provides input to the physiological system that is to be controlled.Output from the system is monitored in a patient using sensors forphysiological signals. Those signals may then be used to providefeedback to the controller.

In closed-loop mode, the controller and system are used to selectparameters for the vagus nerve stimulation. Closed loop mode may also beused when the physiological system is non-stationary. Otherwise, thecontroller may be used to forecast the imminence of an acute event, andthe vagus nerve stimulator is used in open loop mode to stimulate thepatient, but using stimulator parameters that had been selected when thesystem was used in closed-loop mode.

Forecasting models may be grey-box models that incorporate knowledge ofthe physiological system's anatomy and mechanisms. Forecasting modelsmay also be black box models, comprising autoregressive models as wellas models that make use of principal components, Kalman filters, wavelettransforms, hidden Markov models, artificial neural networks, and/orsupport vector machines. In the preferred embodiments, support vectormachines are used.

Methods are disclosed wherein an imminent asthma attack is averted byforecasting the attack and using noninvasive vagus nerve stimulation. Agrey-box forecasting model involving coupled Duffing oscillators isdisclosed. The model predicts the abrupt onset of asthma, which isdescribed in terms of phase diagrams. Data used to fit parameters of themodel include a those acquired by an environmental sensor as well asimages of the lung acquired by electrical impedance tomography andacoustic imaging. Alternatively, a black box model may be used to makethe forecast, based upon data acquired using any of the sensorsmentioned above.

Methods are disclosed wherein an imminent epileptic seizure is avertedby forecasting the attack and using noninvasive vagus nerve stimulation.Data used to forecast the seizure may include those acquired by EEG,electrodermal measurement , heart rate variability, or any of the othersensors mentioned above.

Methods are disclosed wherein an imminent migraine headache is avertedby forecasting the headache and using noninvasive vagus nervestimulation. Data used to forecast the migraine headache may includethose acquired from sensors for stress, cardiovascular and respiratorysensors, transdermal reverse iontophoresis sensors, environmentalsensors, and brain function sensors, or any of the other sensorsmentioned above.

Methods are disclosed wherein an imminent transient ischemic attack(TIA) or a stroke is averted by forecasting the TIA or stroke and usingnoninvasive vagus nerve stimulation. Data used to forecast the TIA orstroke include those acquired using transcranial Doppler ultrasound, orany of the other sensors mentioned above.

Methods are disclosed wherein imminent atrial fibrillation is averted byforecasting the atrial fibrillation and using noninvasive vagus nervestimulation. Data used to forecast the atrial fibrillation include thoseacquired from an electrocardiogram, or any of the other sensorsmentioned above.

Methods are disclosed wherein an imminent myocardial infarction isaverted by forecasting the myocardial infarction and using noninvasivevagus nerve stimulation. Data used to forecast the myocardial infarctioninclude those acquired using radio-labeled probes and a vest containinga nuclear detector, or any of the other sensors mentioned above.

Methods are disclosed wherein imminent ventricular fibrillation orventricular tachycardia is averted by forecasting the ventricularfibrillation or tachycardia and using noninvasive vagus nervestimulation. Data used to forecast the ventricular fibrillation includethose acquired from an electrocardiogram, or any of the other sensorsmentioned above.

Methods are disclosed wherein an imminent panic attack is averted byforecasting the panic attack and using noninvasive vagus nervestimulation. Data used to forecast the panic attack include sensors forstress, as well as cardiovascular and respiratory sensors, or any of theother sensors mentioned above.

Methods are disclosed wherein an imminent attack of depression isaverted by forecasting the depression attack and using noninvasive vagusnerve stimulation. Data used to forecast the attack of depressioninclude sensors for stress, as well as cardiovascular and respiratorysensors, or any of the other sensors mentioned above.

However, it should be understood that application of the methods anddevices is not limited to the examples that are given. The novelsystems, devices and methods for treating conditions using the disclosedstimulator or other non-invasive stimulation devices are more completelydescribed in the following detailed description of the invention, withreference to the drawings provided herewith, and in claims appendedhereto. Other aspects, features, advantages, etc. will become apparentto one skilled in the art when the description of the invention hereinis taken in conjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1A is a schematic view of a magnetic-based nerve or tissuemodulating device according to the present invention, which suppliescontrolled pulses of electrical current to magnetic coils, each of whichare continuously in contact with a volume filled with electricallyconducting material, and wherein the conducting material is also incontact with an interface element that, in operation, contacts thepatient's skin.

FIG. 1B is a schematic view of an electrode-based nerve or tissuemodulating device according to the present invention, which suppliescontrolled pulses of electrical current to electrodes, each of which arecontinuously in contact with a volume filled with electricallyconducting material, and wherein the conducting material is also incontact with an interface element that, in operation, contacts thepatient's skin.

FIG. 2A, 2B and 2C illustrate an exemplary electrical voltage/currentprofiles for blocking and/or modulating impulses that are applied to aportion or portions of a nerve, in accordance with an embodiment of thepresent invention.

FIG. 3A illustrates a dual-electrode stimulator according to anembodiment of the present invention, which is shown to house thestimulator's electrodes and electronic components.

FIG. 3B illustrates a cut-a-way view of the dual-electrode stimulatorshown in FIG. 3A.

FIG. 4A is an exploded view of one embodiment of the head of adual-electrode stimulator that is shown in FIGS. 3A and 3B.

FIG. 4B is a completed assembly view of the head of FIG. 4A.

FIG. 4C is an exploded view of an alternative embodiment of the head ofFIG. 4A.

FIG. 4D is a completed assembly view of the head of FIG. 4C.

FIG. 4E is an exploded view of another alternative embodiment of thehead of FIG. 4A.

FIG. 4F is a completed assembly view of the head of FIG. 4E.

FIG. 5A is a top view of an alternate embodiment of the dual-electrodestimulator of FIGS. 3A and 3B.

FIG. 5B is a bottom view of the dual-electrode stimulator of FIG. 5A.

FIG. 5C is a cut-a-way view of the top of the dual-electrode stimulatorof FIG. 5A.

FIG. 5D is a cut-a-way view of the bottom of the dual-electrodestimulator of FIG. 5A.

FIG. 6 illustrates the approximate position of the housing of thedual-electrode stimulator according one embodiment of the presentinvention, when the electrodes are used to stimulate a vagus nerve inthe neck of a patient.

FIG. 7 illustrates the housing of the dual-electrode stimulatoraccording one embodiment of the present invention, as the electrodes arepositioned to stimulate a vagus nerve in a patient's neck, such that thestimulator is applied to the surface of the neck in the vicinity of theidentified anatomical structures.

FIG. 8 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

FIG. 9A illustrates a phase diagram according to the present invention,which circumscribes regions where coupled bronchiolar nonlinearoscillators within the lung exhibit qualitatively different types ofdynamics, as the concentration environmental signals and cumulativemagnitude of vagus nerve stimulations are varied.

FIG. 9B illustrates the dynamics of the phases in the diagram of FIG.9A.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, energy is transmitted non-invasively to apatient using novel electrode-based and/or magnetic stimulation devicesthat are designed to meet a long-felt but unsolved need to stimulatenerves electrically, totally non-invasively, selectively, andessentially without producing pain.

The invention is particularly useful for producing applied electricalimpulses that interact with the signals of one or more nerves to achievea therapeutic result. In particular, the present disclosure describesdevices and methods to stimulate a vagus nerve non-invasively at alocation in the neck, in order to avert an imminent medical attack.

Transcutaneous electrical stimulation with electrodes, as well as withmagnetic stimulators, can be unpleasant or painful, in the experience ofpatients that undergo such procedures. The quality of sensation causedby stimulation depends strongly on current and frequency, such thatcurrents barely greater than the perception threshold generally causepainless sensations described as tingle, itch, vibration, buzz, touch,pressure, or pinch, but higher currents can cause sharp or burning pain.As the depth of penetration of the stimulus under the skin is increased,any pain will generally begin or increase. Strategies to reduce the paininclude: use of anesthetics placed on or injected into the skin near thestimulation and placement of foam pads on the skin at the site ofstimulation [Jeffrey J. BORCKARDT, Arthur R. Smith, Kelby Hutcheson,Kevin Johnson, Ziad Nahas, Berry Anderson, M. Bret Schneider, Scott T.Reeves, and Mark S. George. Reducing Pain and Unpleasantness DuringRepetitive Transcranial Magnetic Stimulation. Journal of ECT 2006;22:259-264], use of nerve blockades [V. HAKKINEN, H. Eskola, A.Yli-Hankala, T. Nurmikko and S. Kolehmainen. Which structures aresensitive to painful transcranial stimulation? Electromyogr. clin.Neurophysiol. 1995, 35:377-383], the use of very short stimulationpulses [V. SUIHKO. Modelling the response of scalp sensory receptors totranscranial electrical stimulation. Med. Biol. Eng. Comput., 2002, 40,395-401], decreasing current density by increasing electrode size[Kristof VERHOEVEN and J. Gert van Dijk. Decreasing pain in electricalnerve stimulation. Clinical Neurophysiology 117 (2006) 972-978], using ahigh impedance electrode [N. SHA, L. P. J. Kenney, B. W. Heller, A. T.Barker, D. Howard and W. Wang. The effect of the impedance of a thinhydrogel electrode on sensation during functional electricalstimulation. Medical Engineering & Physics 30 (2008): 739-746] andproviding patients with the amount of information that suits theirpersonalities [Anthony DELITTO, Michael J Strube, Arthur D Shulman,Scott D Minor. A Study of Discomfort with Electrical Stimulation. Phys.Ther. 1992; 72:410-424]. Patent U.S. Pat. No. 7,614,996, entitledReducing discomfort caused by electrical stimulation, to RIEHL disclosesthe application of a secondary stimulus to counteract what wouldotherwise be an uncomfortable primary stimulus. Other methods ofreducing pain are intended to be used with invasive nerve stimulation[Patent No. U.S. Pat. No. 7,904,176, entitled Techniques for reducingpain associated with nerve stimulation, to BEN-EZRA et al].

Additional considerations related to pain resulting from the stimulationare as follows. When stimulation is repeated over the course of multiplesessions, patients may adapt to the pain and exhibit progressively lessdiscomfort. Patients may be heterogeneous with respect to theirthreshold for pain caused by stimulation, including heterogeneityrelated to gender and age. Electrical properties of an individual's skinvary from day to day and may be affected by cleaning, abrasion, and theapplication of various electrode gels and pastes. Skin properties mayalso be affected by the stimulation itself, as a function of theduration of stimulation, the recovery time between stimulation sessions,the transdermal voltage, the current density, and the power density. Theapplication of multiple electrical pulses can result in differentperception or pain thresholds and levels of sensation, depending on thespacing and rate at which pulses are applied. The separation distancebetween two electrodes determines whether sensations from the electrodesare separate, overlap, or merge. The limit for tolerable sensation issometimes said to correspond to a current density of 0.5 mA/cm², but inreality the functional relationship between pain and current density isvery complicated. Maximum local current density may be more important inproducing pain than average current density, and local current densitygenerally varies under an electrode, e.g., with greater currentdensities along edges of the electrode or at “hot spots.” Furthermore,pain thresholds can have a thermal and/or electrochemical component, aswell as a current density component. Pulse frequency plays a significantrole in the perception of pain, with muscle contraction being involvedat some frequencies and not others, and with the spatial extent of thepain sensation also being a function of frequency. The sensation is alsoa function of the waveform (square-wave, sinusoidal, trapezoidal, etc.),especially if pulses are less than a millisecond in duration [Mark R.PRAUSNITZ. The effects of electric current applied to skin: A review fortransdermal drug delivery. Advanced Drug Delivery Reviews 18 (1996):395-425].

Considering that there are so many variables that may influence thelikelihood of pain during non-invasive electrical stimulation (detailedstimulus waveform, frequency, current density, electrode type andgeometry, skin preparation, etc.), considering that these same variablesmust be simultaneously selected in order to independently produce adesired therapeutic outcome by nerve stimulation, and considering thatone also wishes to selectively stimulate the nerve (e.g., avoidstimulating a nearby nerve), it is understandable that prior to thepresent disclosure, no one has described devices and methods forstimulating a nerve electrically, totally non-invasively, selectively,and without causing substantial pain.

Applicant discovered the disclosed electrode-based devices and methodsin the course of experimentation with a magnetic stimulation device thatwas disclosed in Applicant's commonly assigned co-pending U.S. patentapplication Ser. No. 12/964,050 entitled Toroidal Magnetic StimulationDevices and Methods of Therapy, to SIMON et al. Thus, combined elementsin the electrode-based invention do not merely perform the function thatthe elements perform separately (viz., perform therapeutic electricalstimulation or neuromodulation, minimize stimulation pain, or stimulatethe nerve selectively), and one of ordinary skill in the art would nothave combined the claimed elements by known methods because thearchetypal magnetic stimulator was known only to Applicant. Thatstimulator used a magnetic coil, embedded in a safe and practicalconducting medium that was in direct contact with arbitrarily-orientedpatient's skin, which had not been described in its closest art [RafaelCARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering 48 (4, 2001): 434-441; Rafael CarbunaruFAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999. (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor MI)]. Existing magneticstimulators are complex and expensive, use high currents that overheatand limit the possible duration of stimulation, and can producestimulation pain. In contrast to existing magnetic stimulators, thestimulator that was disclosed in Applicant's above-cited co-pendingpatent application is relatively simple to construct and operates withlow currents. Furthermore, the device confines the magnetic field towithin the device itself, so that magnetic fields do not enter thepatient's body. As a result, this design makes it possible to stimulatethe patient's nerve over an extended period of time selectively andwithout producing pain.

FIG. 1A is a schematic diagram of Applicant's above-mentioned magneticnerve stimulating/modulating device 301 for delivering impulses ofenergy to nerves for the treatment of medical conditions. As shown,device 301 may include an impulse generator 310; a power source 320coupled to the impulse generator 310; a control unit 330 incommunication with the impulse generator 310 and coupled to the powersource 320; and a magnetic stimulator coil 341 coupled via wires toimpulse generator coil 310. The stimulator coil 341 is toroidal inshape, due to its winding around a toroid of core material.

Although the magnetic stimulator coil 341 is shown in FIG. 1A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 that is shown in FIG. 1Arepresents all the magnetic stimulator coils of the device collectively.In a preferred embodiment that is discussed in connection with FIG. 5Dbelow, coil 341 actually contains two coils that may be connected eitherin series or in parallel to the impulse generator 310.

The item labeled in FIG. 1A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is discussed below in connection with FIG. 5D, theconducting medium with which the coil 341 is in contact need notcompletely surround the toroid.

The design of the magnetic stimulator 301, which is adapted herein foruse with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a relatively deep nerve suchas a vagus nerve in the patient's neck. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient thanstimulator devices that are currently known in the art. Conversely, fora given amount of pain or discomfort on the part of the patient (e.g.,the threshold at which such discomfort or pain begins), the designachieves a greater depth of penetration of the stimulus under the skin.

FIG. 1B is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either the magnetic stimulator 301or the electrode-based stimulator 302, allowing the user to changeparameter settings depending on whether coils 341 or the electrodes 340are attached.

Although a pair of electrodes 340 is shown in FIG. 1B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 1Brepresent all electrodes of the device collectively.

The item labeled in FIG. 1B as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asdescribed below in connection with embodiments of the invention,conducting medium in which the electrode 340 is embedded need notcompletely surround an electrode. As also described below in connectionwith a preferred embodiment, the volume 350 is electrically connected tothe patient at a target skin surface in order to shape the currentdensity passed through an electrode 340 that is needed to accomplishstimulation of the patient's nerve or tissue. The electrical connectionto the patient's skin surface is through an interface 351. In apreferred embodiment, the interface is made of an electricallyinsulating (dielectric) material, such as a thin sheet of Mylar. In thatcase, electrical coupling of the stimulator to the patient iscapacitive. In other embodiments, the interface comprises electricallyconducting material, such as the electrically conducting medium 350itself, or an electrically conducting or permeable membrane. In thatcase, electrical coupling of the stimulator to the patient is ohmic. Asshown, the interface may be deformable such that it is form-fitting whenapplied to the surface of the body. Thus, the sinuousness or curvatureshown at the outer surface of the interface 351 corresponds also tosinuousness or curvature on the surface of the body, against which theinterface 351 is applied, so as to make the interface and body surfacecontiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 340. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER, both of which areincorporated herein by reference, relating to stimulation of neurons ofthe sympathetic nervous system to attenuate an immune response, containdescriptions of pulse generators that may be applicable to the presentinvention. By way of example, a pulse generator is also commerciallyavailable, such as Agilent 33522A Function/Arbitrary Waveform Generator,Agilent Technologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif.95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard and computer mouse as wellas any externally supplied physiological signals (see FIG. 8),analog-to-digital converters for digitizing externally supplied analogsignals (see FIG. 8), communication devices for the transmission andreceipt of data to and from external devices such as printers and modemsthat comprise part of the system, hardware for generating the display ofinformation on monitors that comprise part of the system, and busses tointerconnect the above-mentioned components. Thus, the user may operatethe system by typing instructions for the control unit 330 at a devicesuch as a keyboard and view the results on a device such as the system'scomputer monitor, or direct the results to a printer, modem, and/orstorage disk. Control of the system may be based upon feedback measuredfrom externally supplied physiological or environmental signals.Alternatively, the control unit 330 may have a compact and simplestructure, for example, wherein the user may operate the system usingonly an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes or coils, as well as the spatialdistribution of the electric field that is produced by the electrodes orcoils. The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes or coils, as well as bythe anatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmurto, Przemystaw Ptonecki, JacekStarzynski, Stanislaw Wincenciak, Andrzej Rysz. Mathematical Modellingof Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A. ElectromagneticField, Health and Environment: Proceedings of EHE'07. Amsterdam, 105Press, 2008]. Pulses may be monophasic, biphasic or polyphasic.Embodiments of the invention include those that are fixed frequency,where each pulse in a train has the same inter-stimulus interval, andthose that have modulated frequency, where the intervals between eachpulse in a train can be varied.

FIG. 2A illustrates an exemplary electrical voltage / current profilefor a stimulating, blocking and/or modulating impulse applied to aportion or portions of selected nerves in accordance with an embodimentof the present invention. For the preferred embodiment, the voltage andcurrent refer to those that are non-invasively produced within thepatient by the stimulator coils or electrodes. As shown, a suitableelectrical voltage/current profile 400 for the blocking and/ormodulating impulse 410 to the portion or portions of a nerve may beachieved using pulse generator 310. In a preferred embodiment, the pulsegenerator 310 may be implemented using a power source 320 and a controlunit 330 having, for instance, a processor, a clock, a memory, etc., toproduce a pulse train 420 to the coil 341 or electrodes 340 that deliverthe stimulating, blocking and/or modulating impulse 410 to the nerve.Nerve stimulating/modulating device 301 or 302 may be externally poweredand/or recharged or may have its own power source 320. The parameters ofthe modulation signal 400, such as the frequency, amplitude, duty cycle,pulse width, pulse shape, etc., are preferably programmable. An externalcommunication device may modify the pulse generator program to improvetreatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes orcoils, the device disclosed in patent publication No. US2005/0216062 maybe employed, the entire disclosure of which is incorporated herein byreference. That patent publication discloses a multifunctionalelectrical stimulation (ES) system adapted to yield output signals foreffecting electromagnetic or other forms of electrical stimulation for abroad spectrum of different biological and biomedical applications,which produces an electric field pulse in order to non-invasivelystimulate nerves. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape, such as a sine wave, asquare or a saw-tooth wave, or simple or complex pulse, the parametersof which are adjustable in regard to amplitude, duration, repetitionrate and other variables. Examples of the signals that may be generatedby such a system are described in a publication by LIBOFF [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. The signal from the selected generatorin the ES stage is fed to at least one output stage where it isprocessed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.Also included in the system is a measuring stage which measures anddisplays the electrical stimulation signal operating on the substancebeing treated, as well as the outputs of various sensors which senseconditions prevailing in this substance whereby the user of the systemcan manually adjust it or have it automatically adjusted by feedback toprovide an electrical stimulation signal of whatever type the userwishes, who can then observe the effect of this signal on a substancebeing treated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namely,stimulating, blocking and/or modulating some or all of the transmissionof the selected nerve.

For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to 50 Hz, more preferably around 25 Hz. The modulationsignal may have a pulse width selected to influence the therapeuticresult, such as about 20 microseconds or greater, such as about 20microseconds to about 1000 microseconds. For example, the electric fieldinduced by the device within tissue in the vicinity of a nerve is 10 to600 V/m, preferably around 100 V/m. The gradient of the electric fieldmay be greater than 2 V/m/mm. More generally, the stimulation deviceproduces an electric field in the vicinity of the nerve that issufficient to cause the nerve to depolarize and reach a threshold foraction potential propagation, which is approximately 8 V/m at 1000 Hz.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode or coil configuration, andnerve fiber selectivity may be achieved in part through the design ofthe stimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inpatent number U.S. Pat. No. 6,234,953, entitled Electrotherapy deviceusing low frequency magnetic pulses, to THOMAS et al. and applicationnumber US20090299435, entitled Systems and methods for enhancing oraffecting neural stimulation efficiency and/or efficacy, to GLINER etal. One may also vary stimulation parameters iteratively, in search ofan optimal setting [Patent U.S. Pat. No. 7,869,885, entitled Thresholdoptimization for tissue stimulation therapy, to BEGNAUD et al]. However,some stimulation waveforms, such as those described herein, arediscovered by trial and error, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulationof Peripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; Patent U.S. Pat. No. 7,734,340,entitled Stimulation design for neuromodulation, to De Ridder]. However,bursts of sinusoidal pulses are a preferred stimulation waveform, asshown in FIG. 2B and 2C. As seen there, individual sinusoidal pulseshave a period of τ, and a burst consists of N such pulses. This isfollowed by a period with no signal (the inter-burst period). Thepattern of a burst followed by silent inter-burst period repeats itselfwith a period of T. For example, the sinusoidal period τ may be 200microseconds; the number of pulses per burst may be N=5; and the wholepattern of burst followed by silent inter-burst period may have a periodof T=40000 microseconds (a much smaller value of T is shown in FIG. 2Cto make the bursts discernable). When these exemplary values are usedfor T and τ, the waveform contains significant Fourier components athigher frequencies ( 1/200 microseconds=5000/sec), as compared withthose contained in transcutaneous nerve stimulation waveforms, ascurrently practiced.

Applicant is unaware of such a waveform having been used withtherapeutic nerve stimulation, but a similar waveform has been used tostimulate muscle as a means of increasing muscle strength in eliteathletes. However, for the muscle strengthening application, thecurrents used (200 mA) may be very painful and two orders of magnitudelarger than what are disclosed herein. Furthermore, the signal used formuscle strengthening may be other than sinusoidal (e.g., triangular),and the parameters τ, N, and T may also be dissimilar from the valuesexemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, andR. C. Lehman. Electrical stimulation of the quadriceps femoris in anelite weight lifter: a single subject experiment. Int J Sports Med10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation: The Early Experiments. Physical Therapy 82 (10,2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and of Low-Frequency Pulsed Currents on Strength of Contraction, Muscle Fatigue,and Perceived Discomfort. Physical Therapy 88 (10,2008):1167-1176; AlexR WARD. Electrical Stimulation Using Kilohertz-Frequency AlternatingCurrent. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon,M. Prowse, S. Gunda, and J. Batt. The transfer of current through skinand muscle during electrical stimulation with sine, square, Russian andinterferential waveforms. Journal of Medical Engineering and Technology33 (2,2009): 170-181; Patent U.S. Pat. No. 4,177,819, entitled Musclestimulating apparatus, to KOFSKY et al]. Burst stimulation has also beendisclosed in connection with implantable pulse generators, but whereinthe bursting is characteristic of the neuronal firing pattern itself[Patent U.S. Pat. No. 7,734,340 to DE RIDDER, entitled Stimulationdesign for neuromodulation; application US20110184486 to DE RIDDER,entitled Combination of tonic and burst stimulations to treatneurological disorders]. By way of example, the electric field shown inFIGS. 2B and 2C may have an E_(max) value of 17 V/m, which is sufficientto stimulate the nerve but is significantly lower than the thresholdneeded to stimulate surrounding muscle.

A preferred embodiment of the electrode-based stimulator is shown inFIG. 3A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 3B. As shown, the stimulator (30) comprises two heads (31)and a body (32) that joins them. Each head (31) contains a stimulatingelectrode. The body of the stimulator (32) contains the electroniccomponents and battery (not shown) that are used to generate the signalsthat drive the electrodes, which are located behind the insulating board(33) that is shown in FIG. 3B. However, in other embodiments of theinvention, the electronic components that generate the signals that areapplied to the electrodes may be separate, but connected to theelectrode head (31) using wires. Furthermore, other embodiments of theinvention may contain a single such head or more than two heads.

Heads of the stimulator (31) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes (not shown), or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (34) that also serves as an on/off switch. A light(35) is illuminated when power is being supplied to the stimulator. Anoptional cap may be provided to cover each of the stimulator heads (31),to protect the device when not in use, to avoid accidental stimulation,and to prevent material within the head from leaking or drying. Thus, inthis embodiment of the invention, mechanical and electronic componentsof the stimulator (impulse generator, control unit, and power source)are compact, portable, and simple to operate.

Construction of different embodiments of the stimulator head is shown inmore detail in FIG. 4. Referring now to the exploded view shown in FIG.4A, the electrode head is assembled from a snap-on cap (41) that servesas a tambour for a dielectric or conducting membrane (42), a discwithout fenestration (43) or alternatively with fenestration (43′), thehead-cup (44), and the electrode which is also a screw (45). Twoembodiments of the disc (43) are shown. The preferred embodiment (43) isa solid, ordinarily uniformly conducting disc (e.g., metal such asstainless steel), which is possibly flexible in some embodiments. Analternate embodiment of the disc (43′) is also shown, which is anon-conducting (e.g., plastic) aperture screen that permits electricalcurrent to pass through its apertures.

The electrode (45, also 340 in FIG. 1) seen in each stimulator head hasthe shape of a screw that is flattened on its tip. Pointing of the tipwould make the electrode more of a point source, such that the equationsfor the electrical potential may have a solution corresponding moreclosely to a far-field approximation. Rounding of the electrode surfaceor making the surface with another shape will likewise affect theboundary conditions. Completed assembly of the stimulator head is shownin FIG. 4B, which also shows how the head is attached to the body of thestimulator (47).

The membrane (42) ordinarily serves as the interface shown as 351 inFIG. 1. For example, the membrane (42) may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment shown in FIG. 4A,apertures of the alternate disc (43′) may be open, or they may beplugged with conducting material, for example, KM10T hydrogel fromKatecho Inc., 4020 Gannett Ave., Des Moines Iowa 50321. If the aperturesare so-plugged, and the membrane (42) is made of conducting material,the membrane becomes optional, and the plug serves as the interface 351shown in FIG. 1.

The head-cup (44) is filled with conducting material (350 in FIG. 1),for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc., 286Eldridge Rd., Fairfield NJ 07004. The snap-on cap (41), aperture screendisc (43′), head-cup (44) and body of the stimulator are made of anon-conducting material, such as acrylonitrile butadiene styrene. Thedepth of the head-cup from its top surface to the electrode may bebetween one and six centimeters. The head-cup may have a differentcurvature than what is shown in FIG. 4, or it may be tubular or conicalor have some other inner surface geomety that will affect the Neumannboundary conditions.

The alternate embodiment of the stimulator head that is shown in FIG. 4Calso contains a snap-on cap (41), membrane (42) that is made of adielectric or a conducting material, the head-cup (44), and theelectrode which is also a screw (45). This alternate embodiment differsfrom the embodiment shown in FIGS. 4A and 4B in regard to the mechanicalsupport that is provided to the membrane (42). Whereas the disc (43) or(43′) had provided mechanical support to the membrane in the otherembodiment, in the alternate embodiment a reinforcing ring (40) isprovided to the membrane. That reinforcement ring rests onnon-conducting struts (49) that are placed in the head-cup (44), and anon-conducting strut-ring (48) is placed within notches in the struts(49) to hold the struts in place. An advantage of the alternateembodiment is that without a disc (43) or (43′), current flow may beless restricted through the membrane (42), especially if the membrane ismade of a conducting material. Furthermore, although the struts andstrut-ring are made of non-conducting material in this alternateembodiment, the design may be adapted to position additional electrodeor other conducting elements within the head-cup for other morespecialized configurations of the stimulator head, the inclusion ofwhich will influence the electric fields that are generated by thedevice. Completed assembly of the alternate stimulator head is shown inFIG. 4D, without showing its attachment to the body of the stimulator.In fact, it is possible to insert a lead under the head of the electrode(45), and many other methods of attaching the electrode to thesignal-generating electronics of the stimulator are known in the art.

If the membrane (42) is made of conducting materials, and the disc (43)in FIG. 4A is made of solid conducting materials such as stainlesssteel, the membrane becomes optional , and the disc serves as theinterface 351 shown in FIG. 1. Thus, an embodiment without the membraneis shown in FIGS. 4E and 4F. FIG. 4E shows that this version of thedevice comprises a solid (but possibly flexible in some embodiments)conducting disc that cannot absorb fluid (43), the non-conductingstimulator head (44) into or onto which the disc is placed, and theelectrode (45), which is also a screw. It is understood that the disc(43) may have an anisotropic material or electrical structure, forexample, wherein a disc of stainless steel has a grain, such that thegrain of the disc should be rotated about its location on the stimulatorhead, in order to achieve optimal electrical stimulation of the patient.As seen in FIG. 4F, these items are assembled to become a sealedstimulator head that is attached to the body of the stimulator (47). Thedisc (43) may screw into the stimulator head (44), it may be attached tothe head with adhesive, or it may be attached by other methods that areknown in the art. The chamber of the stimulator head-cup is filled witha conducting gel, fluid, or paste, and because the disc (43) andelectrode (45) are tightly sealed against the stimulator head-cup (44),the conducting material within the stimulator head cannot leak out.

In some embodiments, the interface and/or its underlying mechanicalsupport comprise materials that will also provide a substantial orcomplete seal of the interior of the device. This inhibits any leakageof conducting material, such as gel, from the interior of the device andalso inhibits any fluids from entering the device. In addition, thisfeature allows the user to easily clean the outer surface of the device(e.g., with isopropyl alcohol or similar disinfectant), avoidingpotential contamination during subsequent uses of the device.

In some embodiments, the interface comprises a fluid permeable materialthat allows for passage of current through the permeable portions of thematerial. In these embodiments, a conductive medium (such as a gel) ispreferably situated between the electrode(s) and the permeableinterface. The conductive medium provides a conductive pathway forelectrons to pass through the permeable interface to the outer surfaceof the interface and to the patient's skin.

In other embodiments of the present invention, the interface (351 inFIG. 1, or 42 in FIG. 4) is made from a very thin material with a highdielectric constant, such as material used to make capacitors. Forexample, it may be Mylar having a submicron thickness (preferably in therange 0.5 to 1.5 microns) having a dielectric constant of about 3.Because one side of Mylar is slick, and the other side ismicroscopically rough, the present invention contemplates two differentconfigurations: one in which the slick side is oriented towards thepatient's skin, and the other in which the rough side is so-oriented.Thus, at stimulation Fourier frequencies of several kilohertz orgreater, the dielectric interface will capacitively couple the signalthrough itself, because it will have an impedance comparable to that ofthe skin. Thus, the dielectric interface will isolate the stimulator'selectrode from the tissue, yet allow current to pass. In a preferredembodiment of the present invention, non-invasive electrical stimulationof a nerve is accomplished essentially substantially capacitively, whichreduces the amount of ohmic stimulation, thereby reducing the sensationthe patient feels on the tissue surface. This would correspond to asituation, for example, in which at least 30%, preferably at least 50%,of the energy stimulating the nerve comes from capacitive couplingthrough the stimulator interface, rather than from ohmic coupling. Inother words, a substantial portion (e.g., 50%) of the voltage drop isacross the dielectric interface, while the remaining portion is throughthe tissue.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to 5 microns (preferably about 1 micron) with a dielectricconstant of about 3. For a piezoelectric material like barium titanateor PZT (lead zirconate titanate), the thickness could be about 100-400microns (preferably about 200 microns or 0.2 mm), because the dielectricconstant is >1000.

One of the novelties of the embodiment that is a non-invasive capacitivestimulator (hereinafter referred to more generally as a capacitiveelectrode) arises in that it uses a low voltage (generally less than 100volt) power source, which is made possible by the use of a suitablestimulation waveform, such as the waveform that is disclosed herein(FIG. 2B and 2C). In addition, the capacitive electrode allows for theuse of an interface that provides a more adequate seal of the interiorof the device. The capacitive electrode may be used by applying a smallamount of conductive material (e.g., conductive gel as described above)to its outer surface. In some embodiments, it may also be used bycontacting dry skin, thereby avoiding the inconvenience of applying anelectrode gel, paste, or other electrolytic material to the patient'sskin and avoiding the problems associated with the drying of electrodepastes and gels. Such a dry electrode would be particularly suitable foruse with a patient who exhibits dermatitis after the electrode gel isplaced in contact with the skin [Ralph J. COSKEY. Contact dermatitiscaused by ECG electrode jelly. Arch Dermatol 113(1977): 839-840]. Thecapacitive electrode may also be used to contact skin that has beenwetted (e.g., with tap water or a more conventional electrolytematerial) to make the electrode-skin contact (here the dielectricconstant) more uniform [A L ALEXELONESCU, G Barbero, F C M Freire, and RMerletti. Effect of composition on the dielectric properties ofhydrogels for biomedical applications. Physiol. Meas. 31 (2010)S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the this embodiment of thepresent invention (low-voltage, non-invasive capacitive stimulation of anerve), is provided by KELLER and Kuhn, who review the previoushigh-voltage capacitive stimulating electrode of GEDDES et al and writethat “Capacitive stimulation would be a preferred way of activatingmuscle nerves and fibers, when the inherent danger of high voltagebreakdowns of the dielectric material can be eliminated. Goal of futureresearch could be the development of improved and ultra-thin dielectricfoils, such that the high stimulation voltage can be lowered.” [L. A.GEDDES, M. Hinds, and K. S. Foster. Stimulation with capacitorelectrodes. Medical and Biological Engineering and Computing 25(1987):359-360; Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade 18(2,2008):35-45, on page 39]. It is understoodthat in the United States, according to the 2005 National ElectricalCode, high voltage is any voltage over 600 volts. Patents U.S. Pat. No.3,077,884, entitled Electro-physiotherapy apparatus, to BARTROW et al,U.S. Pat. No. 4,144,893, entitled Neuromuscular therapy device, toHICKEY and U.S. Pat. No. 7,933,648, entitled High voltage transcutaneouselectrical stimulation device and method, to TANRISEVER, also describehigh voltage capacitive stimulation electrodes. Patent U.S. Pat. No.7,904,180, entitled Capacitive medical electrode, to JUOLA et al,describes a capacitive electrode that includes transcutaneous nervestimulation as one intended application, but that patent does notdescribe stimulation voltages or stimulation waveforms and frequenciesthat are to be used for the transcutaneous stimulation. Patent U.S. Pat.No. 7,715,921, entitled Electrodes for applying an electric fieldin-vivo over an extended period of time, to PALTI, and U.S. Pat. No.7,805,201, entitled Treating a tumor or the like with an electric field,to PALTI, also describe capacitive stimulation electrodes, but they areintended for the treatment of tumors, do not disclose uses involvingnerves, and teach stimulation frequencies in the range of 50 kHz toabout 500 kHz.

This embodiment of the present invention uses a different method tolower the high stimulation voltage than developing ultra-thin dielectricfoils, namely, to use a suitable stimulation waveform, such as thewaveform that is disclosed herein (FIG. 2B and 2C). That waveform hassignificant Fourier components at higher frequencies than waveforms usedfor transcutaneous nerve stimulation as currently practiced. Thus, oneof ordinary skill in the art would not have combined the claimedelements, because transcutaneous nerve stimulation is performed withwaveforms having significant Fourier components only at lowerfrequencies, and noninvasive capacitive nerve stimulation is performedat higher voltages. In fact, the elements in combination do not merelyperform the function that each element performs separately. Thedielectric material alone may be placed in contact with the skin inorder to perform pasteless or dry stimulation, with a more uniformcurrent density than is associated with ohmic stimulation, albeit withhigh stimulation voltages [L. A. GEDDES, M. Hinds, and K. S. Foster.Stimulation with capacitor electrodes. Medical and BiologicalEngineering and Computing 25(1987): 359-360; Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990,6): 585-619]. With regard to the waveform element, a waveformthat has significant Fourier components at higher frequencies thanwaveforms currently used for transcutaneous nerve stimulation may beused to selectively stimulate a deep nerve and avoid stimulating othernerves, as disclosed herein for both noncapacitive and capacitiveelectrodes. But it is the combination of the two elements (dielectricinterface and waveform) that makes it possible to stimulate a nervecapacitively without using the high stimulation voltage as is currentlypracticed.

Another embodiment of the electrode-based stimulator is shown in FIG. 5,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. In this embodiment, the interface(351 in FIG. 1) is the conducting material itself. FIGS. 5A and 5Brespectively provide top and bottom views of the outer surface of theelectrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5D show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 1B), and thepower-level controller is attached to the control unit (330 in FIG. 1B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 1B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.1B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 1B) to each headcompartment 57. An optional non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another. Although the embodiment in FIG. 5 is shownto be a non-capacitive stimulator, it is understood that it may beconverted into a capacitive stimulator by replacing the mesh openings 51with a dielectric material, such as a sheet of Mylar, or by covering themesh openings 51 with a sheet of such dielectric material.

In a preferred embodiment, the magnetic stimulator coil 341 in FIG. 1Ahas a body that is similar to the electrode-based stimulator shown inFIG. 5C. To compare the electrode-based stimulator with the magneticstimulator, refer to FIG. 5D, which shows the magnetic stimulator 530sectioned along its long axis to reveal its inner structure. Asdescribed below, it reduces the volume of conducting material that mustsurround a toroidal coil, by using two toroids, side-by-side, andpassing electrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near the gapbetween the pair of coils. An additional advantage of using two toroidsin this configuration is that this design will greatly increase themagnitude of the electric field gradient between them, which is crucialfor exciting long, straight axons such as the vagus nerve and certainperipheral nerves.

As seen in FIG. 5D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 1A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 5D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 1A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 1A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 5D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (4,2001): 434-441].

FIG. 5D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 1A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.

As also seen in FIG. 5D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 5C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance. The currents passing throughthe coils of the magnetic stimulator will saturate the core (e.g., 0.1to 2 Tesla magnetic field strength for Supermendur core material). Thiswill require approximately 0.5 to 20 amperes of current being passedthrough each coil, typically 2 amperes, with voltages across each coilof 10 to100 volts. The current is passed through the coils in bursts ofpulses, as described in connection with FIG. 2. Additional disclosure ofthe magnetic stimulator shown in FIG. 1A is provided in Applicant'scommonly assigned co-pending U.S. patent application Ser. No. 12/964,050entitled Toroidal Magnetic Stimulation Devices and Methods of Therapy,to SIMON et al., which is hereby incorporated by reference for allpurposes.

In preferred embodiments of the electrode-based stimulator shown in FIG.1B, electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2,2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J. V. O′Brien, P. A. Grace. An investigationof the effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1,1994):29-35].

For example, there may be more than two electrodes; the electrodes maycomprise multiple concentric rings; and the electrodes may bedisc-shaped or have a non-planar geometry. They may be made of othermetals or resistive materials such as silicon-rubber impregnated withcarbon that have different conductive properties [Stuart F. COGAN.Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng.2008. 10:275-309; Michael F. NOLAN. Conductive differences in electrodesused with transcutaneous electrical nerve stimulation devices. PhysicalTherapy 71(1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 3 to 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran

Bijelic, Nikola Jorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, andDejan B. Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6,2005):448-452; Dejan B. POPOVIC andMirjana B. Popovic. Automatic determination of the optimal shape of asurface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 3to 5 provide a uniform surface current density, which would otherwise bea potential advantage of electrode arrays, and which is a trait that isnot shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stφdkilde-Jφrgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12,2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21(1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6,2006): 368-381;Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman. Imaging ofNonuniform Current Density at Microelectrodes by ElectrogeneratedChemiluminescence. Anal. Chem. 71(1999): 4944-4950]. In fact, patientsfound the design shown in FIGS. 3 to 5 to be less painful in a directcomparison with a commercially available grid-pattern electrode[UltraStim grid-pattern electrode, Axelggard Manufacturing Company, 520Industrial Way, Fall brook Calif., 2011]. The embodiment of theelectrode that uses capacitive coupling is particularly suited to thegeneration of uniform stimulation currents [Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990,6): 585-619].

The electrode-based stimulator designs shown in FIGS. 3 to 5 situate theelectrode remotely from the surface of the skin within a chamber, withconducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [Patent U.S. Pat. No.3,659,614, entitled Adjustable headband carrying electrodes forelectrically stimulating the facial and mandibular nerves, to Jankelson;U.S. Pat. No. 3,590,810, entitled Biomedical body electode, to Kopecky;U.S. Pat. No. 3,279,468, entitled Electrotherapeutic facial maskapparatus, to Le Vine; U.S. Pat. No. 6,757,556, entitled Electrodesensor, to Gopinathan et al; U.S. Pat. No. 4,383,529, entitledIontophoretic electrode device, method and gel insert, to Webster; U.S.Pat. No. 4,220,159, entitled Electrode, to Francis et al. U.S. Pat. No.3,862,633, U.S. Pat. No. 4,182,346, and U.S. Pat. No. 3,973,557,entitled Electrode, to Allison et al; U.S. Pat. No. 4,215,696, entitledBiomedical electrode with pressurized skin contact , to Bremer et al;and U.S. Pat. No. 4,166,457, entitled Fluid self-sealing bioelectrode,to Jacobsen et al.] The stimulator designs shown in FIGS. 3 to 5 arealso self-contained units, housing the electrodes, signal electronics,and power supply. Portable stimulators are also known in the art, forexample, patent U.S. Pat. No. 7,171,266, entitled Electro-acupuncturedevice with stimulation electrode assembly, to Gruzdowich. One of thenovelties of the designs shown in FIGS. 3 to 5 is that the stimulator,along with a correspondingly suitable stimulation waveform, shapes theelectric field, producing a selective physiological response bystimulating that nerve, but avoiding substantial stimulation of nervesand tissue other than the target nerve, particularly avoiding thestimulation of nerves that produce pain.

Examples in the remaining disclosure will be directed to methods forusing the disclosed electrode-based and magnetic stimulation devices fortreating a patient, particularly methods for detecting an imminentadverse event and using the stimulation devices to avert the onset ofthat event. The examples involve stimulating the patient on the surfaceof the patient's neck in order to stimulate one or both of the patient'svagus nerves. However, it will be appreciated that the systems andmethods of the present invention might be applied equally well to othernerves of the body, including but not limited to parasympathetic nerves,sympathetic nerves, and spinal or cranial nerves. For example, thedisclosed devices may be used to treat particular medical conditions oravert medical conditions, comprising not only those described below andthose described in the related applications cited in the section CROSSREFERENCE TO RELATED APPLICATIONS, but also other disorders in which apatient's symptoms may appear abruptly.

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3 to 5 to stimulatethe vagus nerve at that location in the neck, in which the stimulatordevice 50 in FIG. 5 is shown to be applied to the target location on thepatient's neck as described above. For reference, locations of thefollowing vertebrae are also shown: first cervical vertebra 71, thefifth cervical vertebra 75, the sixth cervical vertebra 76, and theseventh cervical vertebra 77.

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin.

The vagus nerve 60 is identified in FIG. 7, along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Features that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65. Additional organs in thevicinity of the vagus nerve include the trachea 66, thyroid gland 67,esophagus 68, scalenus anterior muscle 69, and scalenus medius muscle70. The sixth cervical vertebra 76 is also shown in FIG. 7, with bonystructure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed herein. The position and angular orientation of thedevice are adjusted about that location until the patient perceivesstimulation when current is passed through the stimulator electrodes.The applied current is increased gradually, first to a level wherein thepatient feels sensation from the stimulation. The power is thenincreased, but is set to a level that is less than one at which thepatient first indicates any discomfort. Straps, harnesses, or frames areused to maintain the stimulator in position (not shown in FIG. 6 or 7).The stimulator signal may have a frequency and other parameters that areselected to produce a therapeutic result in the patient. Stimulationparameters for each patient are adjusted on an individualized basis.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2. The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period τ may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation. More generally, there may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of 20 to 1000 microseconds, preferably 200 microseconds. Aburst followed by a silent inter-burst interval repeats at 1 to 5000bursts per second (bps), preferably at 5-50 bps, and even morepreferably 10-25 bps stimulation (10-25 Hz). The preferred shape of eachpulse is a full sinusoidal wave, although triangular or other shapes maybe used as well. The stimulation is then performed typically for 30minutes and the treatment is performed once a week for 12 weeks orlonger. In other situations, the stimulation may be performed for only30 to 120 seconds and repeated only if the patient does not respond tothe first stimulation. However, it is understood that parameters of thestimulation protocol may be varied in response to heterogeneity in thepathophysiology of patients.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a time-varying sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect. For example, thehypothalamus is well known to be responsive to the presence of brightlight, so exposing the patient to bright light that is fluctuating withthe same stimulation frequency as the vagus nerve (or a multiple of thatfrequency) may be performed in an attempt to enhance the role of thehypothalamus in producing the desired therapeutic effect. Such pairedstimulation does not necessarily rely upon neuronal plasticity and is inthat sense different from other reports of paired stimulation [Navzer D.ENGINEER, Jonathan R. Riley, Jonathan D. Seale, Will A. Vrana, Jai A.Shetake, Sindhu P. Sudanagunta, Michael S. Borland and Michael P.Kilgard. Reversing pathological neural activity using targetedplasticity. Nature 470(7332,2011):101-4].

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of pain or muscle twitches. Ordinarily,the amplitude of the stimulation signal is set to the maximum that iscomfortable for the patient, and then the other stimulation parametersare adjusted. Alternatively, the selection of parameter values mayinvolve tuning as understood in control theory, and as described below.It is understood that parameters may also be varied randomly in order tosimulate normal physiological variability, thereby possibly inducing abeneficial response in the patient [Buchman TG. Nonlinear dynamics,complex systems, and the pathobiology of critical illness. Curr OpinCrit Care 10(5,2004):378-82].

Use of the Stimulators in Conjunction with Controllers

Individualized treatment may be based on the methods that will now bedescribed in connection with the use of control theory to selectstimulation parameters. In brief, the patient's physiological andmedical state are modeled a set of differential equations, for example,as coupled nonlinear oscillators; measurements concerning the patient'sfunction are made preferably using ambulatory measurement sensors suchas those described herein; parameters of the equations are estimatedusing the measurements, including measurement of the patient's functionfollowing stimulation with different parameters that may be used for thestimulation protocol; and a treatment protocol (set of stimulationparameters) is selected in nearly real- time that will provide the bestoutcome and avoid or ameliorate the effects of undesired events.

For example, if it is desired to maintain a constant stimulation in thevicinity of the vagus nerve (or any other nerve or tissue that is beingstimulated), control theory methods may be employed to modulate thepower of the stimulator in order to compensate for patient motion orother mechanisms that would otherwise give rise to variability in thepower of stimulation. In the case of stimulation of the vagus nerve,such variability may be attributable at least to the patient'sbreathing, which may involve contraction and associated change ingeometry of the sternocleidomastoid muscle that is situated close to thevagus nerve (identified as 65 in FIG. 7). Such modulation may beaccomplished using controllers (e.g. PID controllers) that are known inthe art of control theory, as now described.

FIG. 8 is a control theory representation of the disclosed vagus nervestimulation methods, used not only to maintain a constant stimulation,but also used in connection with the selection of stimulation parametersand stimulation protocols as described below. As shown in FIG. 8, thepatient, or the relevant physiological component of the patient, isconsidered to be the “System” that is to be controlled. The “System”(patient) receives input from the “Environment.” For example, in thecase of an asthmatic, the environment would include breathed irritants;or in the case of a migraineur, the environment may include flickeringor bright light that could trigger an aura. If the “System” is definedto be only a particular physiological component of the patient, the“Environment” may also be considered to include physiological systems ofthe patient that are not included in the “System”. Thus, if somephysiological component can influence the behavior of anotherphysiological component of the patient, but not vice versa, the formercomponent could be part of the environment and the latter could be partof the system. On the other hand, if it is intended to control theformer component to influence the latter component, then both componentsshould be considered part of the “System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may include thecontrol unit 330 in FIG. 1. Feedback in the schema shown in FIG. 8 ispossible because physiological measurements of the System are made usingsensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller. Asdescribed in the Background of the Invention section to this disclosure,the preferred sensors will be ordinarily used for ambulatory monitoring,selected to characterize the components of the patient's physiology thatare to be controlled. For example, they may comprise respiratory sensorsfor asthma patients, EEG electrodes for epilepsy patients, ECGelectrodes or blood pressure sensors for cardiac patients, etc.

For situations in which respiratory sensors are used, even if only tocompensate for breathing-related motion of the stimulator, it may alsobe desired to detect the phase of respiration so as to preferentiallyperform or adjust the nerve stimulation during particular parts of therespiratory cycle. Detection of the phase of respiration may beperformed non-invasively by adhering a thermistor or thermocouple probeto the patient's cheek so as to position the probe at the nasal orifice.Strain gauge signals from belts strapped around the chest, as well asinductive plethysmography and impedance pneumography, are also usedtraditionally to non-invasively generate a signal that rises and fallsas a function of the phase of respiration. After digitizing suchsignals, the phase of respiration may be determined using software suchas “puka”, which is part of PhysioToolkit, a large published library ofopen source software and user manuals that are used to process anddisplay a wide range of physiological signals [GOLDBERGER A L, Amaral LA N, Glass L, Hausdorff J M, Ivanov PCh, Mark R G, Mietus J E, Moody GB, Peng C K, Stanley H E. PhysioBank, PhysioToolkit, and PhysioNet:Components of a New Research Resource for Complex Physiologic Signals.Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T.Room E25-505A, 77 Massachusetts Avenue, Cambridge, Mass. 02139. In oneembodiment of the present invention, the control unit 330 contains ananalog-to-digital converter to receive such analog respiratory signals,and software for the analysis of the digitized respiratory waveformresides within the control unit 330. That software extracts turningpoints within the respiratory waveform, such as end-expiration andend-inspiration, and forecasts future turning-points, based upon thefrequency with which waveforms from previous breaths match a partialwaveform for the current breath. The control unit 330 then controls theimpulse generator 310, for example, to stimulate or adjust stimulationof the selected nerve only during a selected phase of respiration, suchas all of inspiration or only the first second of inspiration, or onlythe expected middle half of inspiration.

A related problem is described in patent application JP2008/081479A,entitled Vagus nerve stimulation system, to YOSHIHOTO, wherein a systemis described for keeping the heart rate within safe limits. When theheart rate is too high, that system stimulates a patient's vagus nerve,and when the heart rate is too low, that system tries to achievestabilization of the heart rate by stimulating the heart itself, ratherthan use different parameters to stimulate the vagus nerve. In thatdisclosure, vagal stimulation uses an electrode, which is described aseither a surface electrode applied to the body surface or an electrodeintroduced to the vicinity of the vagus nerve via a hypodermic needle.That disclosure considers stimulation during particular phases of therespiratory cycle, for the following reason. Because the vagus nerve isnear the phrenic nerve, Yoshihoto indicates that the phrenic nerve willsometimes be electrically stimulated along with the vagus nerve. Thepresent applicants have not experienced this problem, so the problem maybe one of a misplaced electrode. In any case, the phrenic nerve controlsmuscular movement of the diaphragm, so consequently, stimulation of thephrenic nerve causes the patient to hiccup or experience irregularmovement of the diaphragm, or otherwise experience discomfort. Tominimize the effects of irregular diaphragm movement, Yoshihoto's systemis designed to stimulate the phrenic nerve (and possibly co-stimulatethe vagus nerve) only during the inspiration phase of the respiratorycycle and not during expiration. Furthermore, the system is designed togradually increase and then decrease the magnitude of the electricalstimulation during inspiration (notably amplitude and stimulus rate) soas to make stimulation of the phrenic nerve and diaphragm gradual.Similarly, it may be desired to perform the vagus nerve stimulation onlyin a particular phase of the cardiac cycle. For example, patentapplication publication US2009/0177252, entitled Synchronization ofvagus nerve stimulation with the cardiac cycle of a patient, to ArthurD. Craig, discloses a method of treating a medical condition in whichthe vagus nerve is stimulated during a portion of the cardiac cycle andthe respiratory cycle.

In situations related to the treatment of asthma, stimulation ofselected nerve fibers during particular phases of respiration may bemotivated by two additional physiological considerations. The first isthat contraction of bronchial smooth muscle appears to be intrinsicallyrhythmic. It has been reported that bronchial smooth muscle contractspreferentially over two phases, during mid-inspiration and earlyexpiration. When the vagus efferent nerves are repetitively stimulatedwith electric pulses, the bronchus constricted periodically; tonicconstriction is almost absent in the bronchus in response to the vagallymediated descending commands [KONDO, Tetsuri, Ichiro Kobayashi, NaokiHayama, Gen Tazaki, and Yasuyo Ohta. Respiratory-related bronchialrhythmic constrictions in the dog with extracorporeal circulation. JAppl Physiol 88(2000): 2031-2036]. Accordingly, a rationale forstimulating the vagus nerve during particular phases of the respiratorycycle is that such stimulation may be used to counteract or inhibit theconstriction that occurs naturally during those specific phases ofrespiration. If the counteracting or inhibiting effects occur only aftera delay, then the timing of the stimulation pulses must precede thephases of respiration during which the contraction would occur, by aninterval corresponding to the delay.

Another motivation for stimulating the vagus nerve during particularphases of respiration is that an increase or decrease in the duration ofsubsequent phases of respiration may be produced by applying thestimulation during particular phases of respiration [M. SAMMON, J. R.Romaniuk and E. N. Bruce. Bifurcations of the respiratory patternproduced with phasic vagal stimulation in the rat. J Appl Physiol75(1993): 912-926]. In particular, a narrow window may exist at theexpiratory-inspiratory transition in which it may be possible to inducebursts of inspiratory activity followed by a prolonged breath.Accordingly, if it is therapeutically beneficial to induce deep breaths,those breaths might be induced by stimulating during that time-window.In fact, the physiologically meaningful cycle of stimulation in thiscase is not a single respiratory cycle, but is instead a collectivesequence of respiratory cycles, wherein it makes sense only to speak ofstimulation during particular parts of the sequence.

In some embodiments of the invention, the potential overheating of themagnetic stimulator coil may also be minimized by optionally restrictingthe magnetic stimulation to particular phases of the respiratory cycle,allowing the coil to cool during the other phases of the respiratorycycle. Alternatively, greater peak power may be achieved per respiratorycycle by concentrating all the energy of the magnetic pulses intoselected phases of the respiratory cycle.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the magnetic stimulator coil or electrodes, in such a wayas to achieve and maintain the heart rate within safe or desired limits.In that case, the parameters of the stimulation are individually raisedor lowered in increments (power, frequency, etc.), and the effect as anincreased, unchanged, or decreased heart rate is stored in the memory ofthe control unit 330. When the heart rate changes to a value outside thespecified range, the control unit 330 automatically resets theparameters to values that had been recorded to produce a heart ratewithin that range, or if no heart rate within that range has yet beenachieved, it increases or decreases parameter values in the directionthat previously acquired data indicate would change the heart rate inthe direction towards a heart rate in the desired range. Similarly, thearterial blood pressure is also recorded non-invasively in an embodimentof the invention (e.g. with a wrist arterial tonometer), and the controlunit 330 extracts the systolic, diastolic, and mean arterial bloodpressure from the blood pressure waveform. The control unit 330 willthen control the impulse generator 310 in such a way as to temporallymodulate nerve stimulation by the magnetic stimulator coil orelectrodes, in such a way as to achieve and maintain the blood pressurewithin predetermined safe or desired limits, by the same method that wasindicated above for the heart rate. Thus, embodiments of the inventiondescribed above may be used to achieve and maintain the heart rate andblood pressure within desired ranges.

The functional form of the system's input is constrained to be as shownin FIG. 2B and 2C. Ordinarily, a parameter that needs adjusting is theone associated with the amplitude of the signal shown in FIG. 2. As afirst example of the use of feedback to control the system, consider theproblem of adjusting the input from the vagus nerve stimulator (i.e.,output from the controller) in order to compensate for motion of thestimulator relative to a vagus nerve.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error in the intended versus actual nerve stimulation amplitudethat needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr # 300Coppell, Tex. 75019. One or more accelerometer is attached to thepatient's neck, and one or more accelerometer is attached to the head ofthe stimulator in the vicinity of where the stimulator contacts thepatient. Because the temporally integrated outputs of the accelerometersprovide a measurement of the current position of each accelerometer, thecombined accelerometer outputs make it possible to measure any movementof the stimulator relative to the underlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1,1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed to perform neck movements,breathe deeply so as to contract the sternocleidomastoid muscle, andgenerally simulate possible motion that may accompany prolongedstimulation with the stimulator. This would include possible slippage ormovement of the stimulator relative to an initial position on thepatient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurto,Przemystaw Ptonecki, Jacek Starzyński, Stanislaw Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator in proportion to the inferred deviation ofthe amplitude of the electric field in the vicinity of the vagus nerve,relative to its desired value.

Now consider the more general problem of controlling the stimulator insuch a way as to maintain a measured physiological variable within adesired range. Let the measured output variables of the system in FIG. 8be denoted by y_(i)(i=1 to Q); let the desired (reference or setpoint)values of y_(i) be denoted by r_(i) and let the controller's input tothe system consist of variables u_(j)(j=1 to P). The objective is for acontroller to select the input u_(j) in such a way that the outputvariables (or a subset of them) closely follows the reference signalsr_(i), i.e., the control error e_(i)=r_(i)−y_(i) is small, even if thereis environmental input or noise to the system. Consider the errorfunction e_(i)=r_(i)−y_(i) to be the sensed physiological input to thecontroller in FIG. 8 (i.e., the reference signals are integral to thecontroller, which subtracts the measured system values from them toconstruct the control error signal). The controller will also receive aset of measured environmental signals v_(k)(k=1 to R), which also actupon the system as shown in FIG. 8.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t,{y_(i)},{u_(j)},{v_(k)};{r_(j)}), where t is time andwhere in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form: μ(t)=K_(p)e(t)+K_(t)∫₀^(t)e(τ)dτ+K_(d) _(dt/) ^(da) where the parameters for the controllerare the proportional gain (K_(p)), the integral gain (K_(d)) and thederivative gain (K_(d)). This type of controller, which forms acontrolling input signal with feedback using the error e=r−y, is knownas a PID controller (proportional-integral-derivative).

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [L I, Y., Ang, K. H. and Chong, G. C. Y. Patents, softwareand hardware for PID control: an overview and analysis of the currentart. IEEE Control Systems Magazine, 26 (1,2006): 42-54; Karl JohanAstrom & Richard M. Murray.Feedback Systems: An Introduction forScientists and Engineers. Princeton NJ:Princeton University Press, 2008;Finn HAUGEN. Tuning of PID controllers (Chapter 10) In: Basic Dynamicsand Control. 2009. ISBN 978-82-91748-13-9. TechTeach, Enggravhφgda 45,N-3711 Skien, Norway. http://techteach.no., pp. 129-155; Dingyu X U E,YangQuan Chen, Derek P. Atherton. PID controller design (Chapter 6), In:Linear Feedback Control: Analysis and Design with MATLAB. Society forIndustrial and Applied Mathematics (SIAM).3600 Market Street, 6thFloor,Philadelphia, Pa. (2007), pp. 183-235; Jan JANTZEN, Tuning OfFuzzy PID Controllers, Technical University of Denmark, report 98-H 871,Sep. 30, 1998].

Commercial versions of PID controllers are available, and they are usedin 90% of all control applications. However, performance of systemcontrol can be improved by combining the feedback closed-loop control ofa PID controller with feed-forward control, wherein knowledge about thesystem's future behavior can be fed forward and combined with the PIDoutput to improve the overall system performance. For example, if thesensed environmental input in FIG. 8 is such the environmental input tothe system will have a deleterious effect on the system after a delay,the controller may use this information to provide anticipatory controlinput to the system, so as to avert or mitigate the deleterious effectsthat would have been sensed only after-the-fact with a feedback-onlycontroller.

Because the present invention is concerned with anticipating andaverting acute medical events, the controller shown in FIG. 8 willpreferably make use of feed-forward methods [Coleman BROSILOW, BabuJoseph. Feedforward Control (Chapter 9) In: Techniques of Model-BasedControl. Upper Saddle River, N.J: Prentice Hall PTR,2002. pp, 221-240].Thus, the controller in FIG. 8 is preferably a type of predictivecontroller, methods for which have been developed in other contexts aswell, such as when a model of the system is used to calculate futureoutputs of the system, with the objective of choosing among possibleinputs so as to optimize a criterion that is based on future values ofthe system's output variables (e.g. minimum cost, safety, qualitycontrol or performance). An analogy distinguishing feedback andfeedforward controllers is that with the former, a thermostat will turnon a heater when the room temperature drops below a setpoint (feedback),but a feedforward controller may turn on the heater when the room'soutside door is opened, even before the room temperature has droppedsignificantly.

A mathematical model of the system is needed in order to perform thepredictions of system behavior, for purposes of including thepredictions in a feedforward control device. Models that are completelybased upon physical first principles (white-box) are rare, especially inthe case of physiological systems. Instead, most models that make use ofprior structural and mechanistic understanding of the system areso-called grey-box models, one of which is described below in connectionwith the forecasting of asthma attacks. Another example of a grey-boxmodel was disclosed in the co-pending, commonly assigned applicationSer. No. 13/279,437, filed Oct. 24, 2011, Titled NON-INVASIVE ELECTRICALAND MAGNETIC NERVE STIMULATORS USED TO TREAT OVERACTIVE BLADDER ANDURINARY INCONTINENCE, herein incorporated by reference in theirentirety. If the mechanisms of the systems are not sufficientlyunderstood in order to construct a white or grey box model, a black-boxmodel may be used instead. Such models comprise autoregressive models[Tim BOLLERSLEV. Generalized autoregressive condiditionalheteroskedasticity. Journal of Econometrics 31(1986):307-327], or thosethat make use of principal components [James H. STOCK, Mark W. Watson.Forecasting with Many Predictors, In: Handbook of Economic Forecasting.Volume 1,G. Elliott, C. W. J. Granger and A. Timmermann,eds (2006)Amsterdam: Elsevier B. V, pp 515-554], Kalman filters [Eric A. WAN andRudolph van der Merwe. The unscented Kalman filter for nonlinearestimation, In: Proceedings of Symposium 2000 on Adaptive Systems forSignal Processing, Communication and Control (AS-SPCC) , IEEE, LakeLouise, Alberta, Canada, Oct, 2000, pp 153-158], wavelet transforms [O.RENAUD, J.-L. Stark, F. Murtagh. Wavelet-based forecasting of short andlong memory time series. Signal Processing 48(1996):51-65], hiddenMarkov models [Sam ROWEIS and Zoubin Ghahramani. A Unifying Review ofLinear Gaussian Models. Neural Computation 11(2,1999): 305-345], orartificial neural networks [Guoquiang ZHANG, B. Eddy Patuwo, Michael Y.Hu. Forecasting with artificial neural networks: the state of the art.International Journal of Forecasting 14(1998): 35-62].

For the present invention, a grey-box model is preferred, but if ablack-box model must be used instead, the preferred model will be onethat makes use of support vector machines. A support vector machine(SVM) is an algorithmic approach to the problem of classification withinthe larger context of supervised learning. A number of classificationproblems whose solutions in the past have been solved by multi-layerback-propagation neural networks, or more complicated methods, have beenfound to be more easily solvable by SVMs. In the present context, atraining set of physiological data will have been acquired that includeswhether or not the patient is experiencing some type of acute attack.Thus, the classification of the patient's state is whether or not anattack is in progress, and the data used to make the classificationconsist of the remaining acquired physiological data, evaluated at Δtime units prior to the time at which the attack data are acquired.Thus, the SVM is trained to forecast the imminence of an attack Δ timeunits into the future. After training the SVM, it is implemented as partof the controller to sound an alarm and advise the use of vagal nervestimulation, whenever there is a forecast of an imminent attack[Christopher J. C. BURGES. A tutorial on support vector machines forpattern recognition. Data Mining and Knowledge Discovery 2(1998),121-167; J. A. K. Suykens, J. Vandewalle, B. De Moor. Optimal Control byLeast Squares Support Vector Machines. Neural Networks 14 (2001):23-35;Sapankevych, N.and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine4(2,2009): 24-38; Press, W H; Teukolsky, S A; Vetterling, W T; Flannery,B P (2007). Section 16.5. Support Vector Machines. In: NumericalRecipes: The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press].

Although classical control theory works well for linear systems havingone or only a few system variables, special methods have been developedfor systems in which the system is nonlinear (i.e., the state-spacerepresentation contains nonlinear differential equations), or multipleinput/output variables. Such methods are important for the presentinvention because the physiological system to be controlled will begenerally nonlinear, and there will generally be multiple outputphysiological signals. It is understood that those methods may also beimplemented in the controller shown in FIG. 8 [Torkel GLAD and LennartLjung. Control Theory. Multivariable and Nonlinear Methods. New York:Taylor and Francis, 2000; Zdzislaw BUBNICKI. Modern Control Theory.Berlin: Springer, 2005].

Now consider the problem of adjusting the input u(t) from the vagusnerve stimulator (i.e., output from the controller) in order to maintaina desired output from the system, wherein the desired output keeps aphysiological variable within a specified range. Examples given aboveinclude keeping the heart rate and blood pressure within desired ranges.Another example involving the treatment of asthma patients was addressedin the co-pending, commonly assigned application no. 12/859,568 filedAug. 19, 2010, entitled NON-INVASIVE TREATMENT OF BRONCHIALCONSTRICTION. As described there, the objective was to maintain theforced expiratory volume in one second (FEV₁) or an alternate lungfunction index FEV₁%VC at a predetermined value, using vagus nervestimulation. Instead of using actual measurement of FEV₁, it wasdisclosed that surrogate measurements of FEV₁ could also be made,namely, pulsus paradoxus, accessory muscle use or airway resistance(Rint). Methods for obtaining signals proportional to those surrogateswere described. For those measurements that give intermittent readings,interpolation may be used to construct a continuous surrogate signal,which may be designated as the system output y(t). It may be preferredto maintain the surrogate reading at some value r=y₀, but it may bedifficult to maintain that constancy, such that there will usually besome error e=r−y in the surrogate value of FEV₁ that needs continuousadjustment. To compensate for that error, rather than adjust theamplitude or other parameters of the stimulator manually, one may usethe PID that was described above, wherein the gains of the PID are tunedaccording to the Ziegler-Nichols or other rules. Thereafter, the PIDadjusts the amplitude automatically so as to best maintain the patient'sFEV₁ or surrogate value at a preferred value. The default amplitudeparameter is then reset according to its average value over time, as thePID continuously adjusts the value of the input u(t) thorough adjustmentof the stimulator signal's amplitude (and any other parameters that mayhave been tuned). It is understood that this adjustment of thestimulation parameters is in addition to, or combined with, othercontrol tasks such as compensating for movement of the stimulatorrelative to the vagus nerve.

A different strategy for selecting the parameters in FIG. 2 may also beused, in which several alternate sets of stimulator values are availablefor use. This strategy would be used when the physiological systemitself is not stationary. For example, brain waves detected with an EEGmay at one time have certain semi-stationary characteristics, but at alater time, they may have different semi-stationary characteristics,which in either case may be modulated to desired setpoints bystimulating the patient with the vagus nerve stimulator. The effects ofvagus nerve stimulation on surface EEG waveforms may be difficult todetect [Michael BEWERNITZ, Georges Ghacibeh, Onur Seref, Panos M.Pardalos, Chang-Chia Liu, and Basim Uthman. Quantification of the impactof vagus nerve stimulation parameters on electroencephalographicmeasures. AIP Conf. Proc. DATA MINING, SYSTEMS ANALYSIS AND OPTIMIZATIONIN BIOMEDICINE; Nov. 5, 2007, Volume 953, pp. 206-219], but they mayexist nevertheless [K00 B. EEG changes with vagus nerve stimulation. JClin Neurophysiol. 18(5,2001):434-41; KUBA R, Guzaninová M, Brázdil M,Novak Z, Chrastina J, Rektor I. Effect of vagal nerve stimulation oninterictal epileptiform discharges: a scalp EEG study. Epilepsia.43(10,2002):1181-8; RIZZO P, Beelke M, De Carli F, Canovaro P, Nobili L,Robert A, Fornaro P, Tanganelli P, Regesta G, Ferrillo F. Modificationsof sleep EEG induced by chronic vagus nerve stimulation in patientsaffected by refractory epilepsy. Clin Neurophysiol. 115(3,2004):658-64].If the effects on EEG prove too difficult to measure, the effect ofvagus nerve stimulation on some related variable such as fMRI activationor blood flow in the brain may be measured instead [CHAE JH, Nahas Z,Lomarev M, Denslow S, Lorberbaum JP, Bohning D E, George M S. A reviewof functional neuroimaging studies of vagus nerve stimulation (VNS). JPsychiatr Res. 37(6,2003):443-55; CONWAY C R, Sheline Y I, Chibnall J T,George M S, Fletcher J W, Mintun M A. Cerebral blood flow changes duringvagus nerve stimulation for depression. Psychiatry Res.146(2,2006):179-84]. The semi-stationary brain wave epochs maycorrespond to circadian influences, or to different states of alertness,or they may have an unknown origin. In each epoch, stimulator parametersmay be selected as described above in connection with the FEV₁ control.However, the default parameter values may be different, depending onwhich semi-stationary EEG epoch obtained at the time of PID tuning.Accordingly, when the stimulator is eventually used for prophylactictreatment of a patient, the stimulator should be set to parameter valuesthat are selected to correspond to the semi-stationary EEG epoch thatobtains immediately before stimulation is used for the prophylactictherapy. This is a type of closed-loop application because measurementsof the EEG immediately before therapy are used as “feedback” to selectone of possibly many sets of tuned stimulator parameter values for usein the prophylactic therapy.

Methods for Averting Imminent Asthma Attacks

Once air is inhaled through the mouth or nose, it travels through thetrachea and a progressively subdividing system of bronchi (containingcartilage) and bronchioles (which contain little or no cartilage) untilit finally reaches the alveoli, where the gas exchange of carbon dioxideand oxygen takes place. Through constriction or relaxation of smoothmuscle within their walls, the bronchioles change diameter to eitherincrease or reduce air flow. The bronchioles between the fourth andeighth bifurcation are thought to be most important in that regard. Anincrease in diameter (bronchodilation) is stimulated by epinephrine orsympathetic nerves to increase air flow, and a decrease in diameter(bronchoconstriction) is stimulated by histamine, parasympatheticnerves, cold air, and chemical irritants.

Patients with asthma experience attacks in which excessive constrictionof the bronchioles make it difficult for them to breathe. Thepathophysiology of asthma, and of the related disorders of chronicobstructive pulmonary disease (COPD) and anaphylaxis, is not fullyunderstood. However, enough is known about asthma to forecast the onsetof an asthma attack, as disclosed below. The objective of this aspect ofthe invention is to avert the forecasted bronchoconstriction by takingprophylactic countermeasures that involve electrical stimulation of thevagus nerve. Other potential countermeasures, such as the administrationof epinephrine, might also be considered [ANDERSON GP. Endotypingasthma: new insights into key pathogenic mechanisms in a complex,heterogeneous disease. Lancet 372(9643,2008): 1107-19; CAIRNS CB. Acuteasthma exacerbations: phenotypes and management. Clin Chest Med.27(1,2006):99-108; RODRIGO GJ. Predicting response to therapy in acuteasthma. Curr Opin Pulm Med. 15(1,2009):35-8]. Individual normalbronchioles undergo constant constriction and dilation, such that thediameters of their lumens may vary considerably over the course of evena few minutes. Normally, some bronchioles are constricting while othersare dilating, but the time-varying heterogeneity of airway caliberthroughout the lung is normally sufficient to bring air to all thealveoli, because any constricted bronchiole would reopen in a relativelyshort period of time. This oscillation of constriction and dilation ofindividual bronchioles throughout the lung leads to physiologicalfluctuations in airway resistance at the level of the whole lung [QUE CL, Kenyon C M, Olivenstein R, Macklem P T, Maksym G N. Homeokinesis andshort-term variability of human airway caliber. J Appl Physiol91(3,2001):1131-41; MUSKULUS M, Slats A M, Sterk P J, Verduyn-Lunel S.Fluctuations and determinism of respiratory impedance in asthma andchronic obstructive pulmonary disease. J Appl Physiol109(6,2010):1582-91; FREY U, Maksym G, Suki B. Temporal complexity inclinical manifestations of lung disease. J Appl Physiol110(6,2011):1723-31]. Accordingly, the present invention describesbronchiole segments mathematically as oscillators, in which a variablecorresponding to each bronchiole segment represents the varying radiusof a bronchiole lumen, minus a value representing a time-averaged radiusin a normal bronchiole. Because segments of the bronchial tree arefluctuating according to the invention, the oscillating branchescollectively give rise to fluctuations in overall respiratory impedance.

It is thought that an asthma attack may correspond to an avalanche ofairway constrictions, in which the constriction in one bronchiolesegment increases the likelihood that another bronchiole branch in thesame tree structure of the lung will constrict. The result is that someinitial heterogeneity of airway constriction within different regions ofthe lung, which might seem to be of little physiological consequence,may actually become amplified by avalanches of airway constrictions,such that eventually large heterogeneous regions of the lung becomeunavailable for normal respiration. Models have been constructed toexplain such heterogeneity and avalanches, but none of them are suitablefor forecasting an imminent asthma attack [ALENCAR A M, Arold S P,Buldyrev S V, Majumdar A, Stamenovic D, Stanley H E, Suki B. Physiology:Dynamic instabilities in the inflating lung. Nature417(6891,2002):809-11; SUKI B, Frey U. Temporal dynamics of recurrentairway symptoms and cellular random walk. J Appl Physiol95(5,2003):2122-7; VENEGAS J G, Winkler T, Musch G, Vidal Melo M F,Layfield D, Tgavalekos N, Fischman AJ , Callahan R J, Bellani G, HarrisR S. Self-organized patchiness in asthma as a prelude to catastrophicshifts. Nature 434(7034,2005):777-82; FREY U, Brodbeck T, Majumdar A,Taylor D R, Town G I, Silverman M, Suki B. Risk of severe asthmaepisodes predicted from fluctuation analysis of airway function. Nature438(7068,2005):667-70; FREY U. Predicting asthma control andexacerbations: chronic asthma as a complex dynamic model. Curr OpinAllergy Clin Immunol 7(3,2007):223-30; MULLALLY W, Betke M, Albert M,Lutchen K. Explaining clustered ventilation defects via a minimal numberof airway closure locations. Ann Biomed Eng 37(2,2009):286-300; POLITI AZ, Donovan G M, Tawhai M H, Sanderson M J, Lauzon A M, Bates J H, SneydJ. A multiscale, spatially distributed model of asthmatic airwayhyper-responsiveness. J Theor Biol 266(4,2010):614-24; TAWHAI M H, BatesJ H. Multi-scale lung modeling. J Appl Physiol 110(5,2011):1466-72; SUKIB, Bates JH. Emergent behavior in lung structure and function. J ApplPhysiol 110(4,2011):1109-10; KACZKA D W, Lutchen KR, Hantos Z. Emergentbehavior of regional heterogeneity in the lung and its effects onrespiratory impedance. J Appl Physiol 110(5,2011):1473-81]. The model oflung dynamics that is disclosed below is able to make such a forecast.It does so by making oscillation of any one bronchiole oscillator afunction of the state of other bronchiole oscillators, as well as afunction of external conditions such as the presence of gas irritantsand electrical stimulation of the vagus nerve.

If feedforward rather than (or in addition to) feedback is to be used tocontrol the system, a feedforward model must be specified. Theparagraphs that follow describe such a feedforward model, which is basedon the observation that bronchial smooth muscle may be oscillating. Theproperties of oscillators are currently understood through the analysisof differential equation prototypes, such as Duffing's oscillator

${{\frac{^{2}y}{t^{2}} + {m\frac{y}{t}} + \frac{P}{y}} = {f(t)}},$

where y is the displacement of the oscillator (e.g., subtracted from avalue representing a time-averaged radius under normal conditions, y₀),m is a damping parameter, P is a potential function of y, and f(t) is adriving function. In the case of respiration, the driving function wouldcorrespond to the flow of air as the respiratory muscles generateinspiration or relax for expiration. The potential function P(y) isoften assumed to satisfy

${\frac{P}{y} = {{by} + {ay}^{3}}},$

where a and b are constants (i.e.,

$\left. {P = {{\frac{b}{2}y^{2}} + {\frac{a}{4}y^{4}}}} \right),$

which for a >0 and b <0 corresponds to a symmetric double-wellpotential. The potential may also be made asymmetric so that it iseasier for the oscillator to reach one well than another, as in

${P = {{\frac{b}{2}y^{2}} + {\frac{a}{4}y^{4}} + {y\left\lbrack {c + {{df}(t)}} \right\rbrack}}},$

where c and d are parameters for asymmetry that is respectivelyindependent of, or dependent on, the driving function f(t). In any case,two types of motion may be seen with such a double-well model: themotion can be confined to one of the wells when a weak driving functionf(t) is applied; or the oscillator can escape a well and visit the otherwell, and vice versa, when a stronger driving function f(t) is applied[O. I. OLUSOLA, U. E. Vincent, A. N. Njah, and J. A. Olowofela.Bistability in coupled oscillators exhibiting synchronized dynamics.Commun. Theor. Phys. 53(2010), pp. 815-824]. If noise is added to thesystem it is possible to convert the former type of motion into thelatter, through a mechanism known as stochastic resonance [LucaGammaitoni, Peter Hanggi, Peter Jung, and Fabio Marchesoni. Stochasticresonance. Rev. Mod. Phys. 70(1998), 223-287].

Duffing's equation describes oscillations in the displacement y that arequalitatively different than those exhibited by a linear, harmonicdriven oscillator. Because it embodies a double-well potential, it isappropriate when a system is preferentially in one of two states, suchas a constricted state versus a dilated state, as in the case of abronchiole oscillator. If there were more than two preferential states,a potential having three or more wells may be assumed, as would be thecase if the bronchiole oscillator had relaxed, dilated, and intermediatestates. A network of coupled oscillators is constructed by making thedisplacement of one oscillator be a function of one or more of the otheroscillators' displacements, i.e., by coupling each oscillator to otheroscillators. Each oscillator in the network can in general havedifferent parameter values, and the network can have different forms oflocal or non-local coupling.

Other well-studied non-linear oscillators include Van der Pol,FitzHugh-Nagumo, Morris-Lecar, Ellias-Grossberg, and Stuart-Landau.Although the detailed oscillations described by such prototypicalequations are dependent on the detailed form of the equations and theirinitial conditions, the qualitative behaviors of such non-linear coupledoscillator equations may often be understood independently of theparticular form of the non-linear equation. For example, it is wellunderstood in general that non-linear oscillators, including a set ofcoupled non-linear oscillators, may exhibit qualitatively differentbehaviors when the parameters of their equations lie within certainbounds. When graphs are drawn showing the value of one parameter on oneaxis, and the value of another parameter on another axis, regions ofthis parameter space may be circumscribed to show what sets of parametervalues correspond to each type of qualitatively different dynamics, i.e,a phase diagram. Examples of such phase diagrams are given by MATTHEWSand STROGATZ, which circumscribe different regions of phase space havingqualitatively different dynamics, and which are also described below inconnection with FIG. 9 [Paul C. MATTHEWS and Steven H. Strogatz. Phasediagram for the collective behavior of limit-cycle oscillators. Phys.Rev. Lett. 65(1990): 1701-1704].

When dealing with coupled nonlinear oscillators, such as coupled Duffingoscillators, the two or more oscillators may eventually all oscillatewith the same phase or they may prefer to oscillate with unrelatedphases, again depending on the range in which the parameter values lie.In the case of a two-well oscillator, the relation between the phase ofdifferent oscillators refers not only to simultaneously occurring peaksand valleys of displacement, but also whether oscillators aresimultaneously trapped in the same potential well. Chimera states, inwhich part of the system is phase locked and simultaneously another partof the system exhibits oscillators with unrelated phases, are alsopossible. Chimera states may be particularly significant in regards tothe regional inhomogeneity of the lung, when one portion of the lungexhibits unrelated phases, and another region exhibits phase locking.These qualitatively different types of dynamic behavior are influencedby the presence of noise, and they are exhibited by nonlinearoscillators generally, of which the Duffing oscillator is only oneexample [GUEVARA M. R. Bifurcations involving fixed points and limitcycles in biological systems. In: Nonlinear Dynamics in Physiology andMedicine, edited by Beuter A., Glass L., Mackey M. C., Titcombe M.S.Springer-Verlag, New York, pp. 41-85 (2003); LEE, Wai Shing; Restrepo,Juan G.; Ott, Edward; Antonsen, Thomas M. Dynamics and pattern formationin large systems of spatially-coupled oscillators with finite responsetimes. Chaos 21 (2, 2011), pp. 023122-023122-14; Hiroshi KORI andAlexander S. Mikhailov. Entrainment of Randomly Coupled OscillatorNetworks by a Pacemaker. Phys. Rev. Lett. 93(2004), 254101, pp 1-4; M.CISZAK, A. Montina, and F. T. Arecchi. Sharp versus smoothsynchronization transition of locally coupled oscillators. Phys. Rev. E78(2008), 016202, pp 1-4; Daniel M. ABRAMS and Steven H. Strogatz.Chimera States for Coupled Oscillators. Phys. Rev. Lett. 93(2004),174102, pp 1-4; KONISHI K. Experimental evidence for amplitude deathinduced by dynamic coupling: van der Pol oscillators. Proc. ISCAS(4,2004) 792-795; Shinji D O I, Yohei Isotani, Ken-ichiro Sugimoto andSadatoshi Kumagai. Noise-induced critical breakdown of phase lockings ina forced van der Pol oscillator. Physics Letters A 310 (5-6, 2003):407-414].

When one or more of the parameters of the set of coupled nonlinearoscillators may be varied under external influences to producequalitative changes of phase in the system, the parameter is said to bean order parameter. According to the present invention, bronchioles ofthe lung may be represented mathematically as nonlinear oscillators thatare coupled to one another, and an order parameter for the system is theconcentration of an environmental lung irritant, as shown in FIG. 9A.Another order parameter is related to the magnitude and duration ofvagus nerve stimulation, which will be described below. Consider firstonly the changes in phase that occur as the concentration of theirritant increases. Moving along the lower axis in FIG. 9A at increasingirritant concentration, the successive phases that are encountered asthe concentration is increased are called successively: phase drift,irregular region, and phase locked. The dynamics of the system in eachof those phases is represented in FIG. 9B, in which the average, overmultiple bronchioles, of bronchiole constriction is shown as a functionof time. For present purposes, bronchial constriction may be defined asthe average of y₀/y, over many bronchioles, where y₀ is a time-averagedradius in a normal bronchiole and y is a bronchiole displacement fromthat radius, such that as y becomes smaller, the constriction becomeslarger.

Within the phase drift phase, there are only small fluctuations ofconstriction amplitude averaged over many bronchioles. This correspondsto a situation in which the bronchioles are oscillating more or lessindependently of one another. Within the irregular phase, there aresmall fluctuations along with occasional irregularly-timed largeamplitude constrictions. The dynamics are not periodic, but may insteadexhibit aperiodic dynamics such as deterministic chaos, Hopfoscillation, quasiperiodicity, and large oscillation [Paul C. MATTHEWSand Steven H. Strogatz. Phase diagram for the collective behavior oflimit-cycle oscillators. Phys. Rev. Lett. 65(1990): 1701-1704; Paul C.MATTHEWS, Renato E. Mirollo, and Steven H. Strogatz. Dynamics of a largesystem of coupled nonlinear oscillators. Physica D: Nonlinear Phenomena52 (2-3,1991): 293-331]. During the phase-locked phase, there are largeamplitude constrictions, as evidenced by the average of the displacementy over many bronchioles. In that phase, the constrictions correspond toalmost all bronchioles in some region(s) of the lung being trapped inone well of the double-well potential, namely, the well corresponding toa constricted bronchiole, as would occur in an asthma attack. However,the lung as a whole may also be in a chimera state, wherein some regionsof the lung are in one phase such as the phase-locked phase, while otherregions of the lung may be in some other phase such as the phase-driftphase, so that not all bronchioles of the lung need be constrictedduring an asthma attack.

Irritant concentrations may be measured non-invasively in real time foran ambulatory patient [Kirk J. ENGLEHARDT and John Toon. Asthma attack:Vest-based sensors monitor environmental exposure to help understandcauses: web page (www) at the Georgia Tech Research Institute (.gtri) ofGeorgia Tech (.gatech) educational domain (.edu) insubdomain:/casestudy/asthma-vest-helps-id-asthma-causes; patentapplication US20110144515, entitled Systems and methods for providingenvironmental monitoring, to BAYER et al.; and patent U.S. Pat. No.7,119,900, entitled Pollen sensor and method, to OKUMURA et al]. Forphysical external irritants, the unit of irritation should be selectedaccordingly, such as temperature for cold air as an irritant.

It is understood, however, that in some patients, external irritanttriggers are hard to identify, and some irritant triggers may well beendogenous substances. In that case, according to the invention, asurrogate for an unknown or endogenous trigger concentration may be theconcentration of exhaled nitric oxide, which can be measurednoninvasively using miniature gas sensors placed in the vicinity of thepatient's mouth [GILL M, Walker S, Khan A, Green S M, Kim L, Gray S,Krauss B. Exhaled nitric oxide levels during acute asthma exacerbation.Acad Emerg Med 12(7,2005):579-86; Oleksandr KUZMYCH, Brett L Allen andAlexander Star. Carbon nanotube sensors for exhaled breath components.Nanotechnology 18 (2007) 375502, pp 1-7]. Accordingly, what is labeledas “Concentration of Environmental Irritants” in FIG. 9 may be replacedby the concentration of any other exogenous or endogenous trigger, or bya surrogate for an asthma trigger.

Referring again to the phase diagram in FIG. 9A, note that the verticalaxis is labeled as “Accumulated Vagus Nerve Stimulation Effects.”According to the present invention, the effectiveness of vagus nervestimulation in inhibiting bronchiole constriction is a function of theelectric field produced by the stimulation and its waveform, theduration of the stimulation, and if stimulation has ceased, the timesince cessation of the last stimulation. Let the numerical value of theaccumulated “Accumulated Vagus Nerve Stimulation Effects” with aparticular stimulation waveform be denoted as S(t). It may for presentpurposes be represented as a function that increases at a rateproportional to the stimulation electric field V at the site of thenerve and decays with a time constant t_(p), such that after prolongedstimulation, the accumulated stimulation effectiveness will saturate ata value equal to the product of V and τ_(p). Thus, if T_(p) is theduration of a vagal nerve stimulation, then for time t<T_(p),S(t)=Vτ_(p) [1−exp(−t/τ_(p))]+S₀ exp(−t/τ_(p)) , and for t>T_(p),S(t)=S(T_(p)) exp (−[t−T_(p)]/τ_(p)), where the time t is measured fromthe start of a stimulus, and S₀ is the value of S when t=0. Then,according to FIG. 9, as electrical stimuli to the vagus nerve areapplied, it is possible for the lung system as a whole to switch fromone phase of bronchial constriction to another, even if the lung isexposed to a constant irritant environment.

For example, if the system begins in the phase locked phase shown inFIG. 9A (asthma attack), it can be simulated up and out of that phaseinto the phase drift phase, and after stimulus ceases, the system willeventually decay back into the phase locked phase (assuming that thepatient's physiology remains stationary). The situation with any givenindividual would depend upon that individual's particular phase diagram,but if the individual has a diagram like the one shown in FIG. 9A, thenthe best strategy for preventing or terminating unwantedbronchoconstriction would be to stimulate the vagus nerve for as long aspossible with as high an electric field as possible, so as to drive thesystem out of its current phase and into the phase drift phase (ormaintain it in the drift phase) for as long as possible. However, thatstrategy may not be practical, because at some electric field, thestimulus would be too painful and would produce side effects. In anyevent, the vagus nerve stimulation is not intended to be continuous, ascould have been the case with an implanted stimulator. Furthermore,because of decay of the accumulated stimulus effect, additionalstimulation may be increasingly ineffective as the effect saturates at alevel determined by the stimulation electric field V and decay timeconstant τ_(p).

Implementation of this model of an asthma attack requires a moredetailed mathematical embodiment of the invention. For example, in oneembodiment, the bronchiole oscillators are represented as coupledDuffing oscillators, as in the following equations with two oscillators.Such a representation can be expanded to any number of oscillators bymaking all oscillators coupled to all other oscillators so as toemphasize neural or humoral feedback loops , or only to oscillators(bronchioles) in proximity to one another so as to emphasize localnearest-neighbor effects, or some intermediate coupling configuration.

${\frac{^{2}y_{1}}{t^{2}} + {m_{1}\frac{y_{1}}{t}} + \frac{P_{1}}{y_{1}}} = {{f_{1}(t)}\mspace{14mu} {and}}$${{\frac{^{2}y_{2}}{t^{2}} + {m_{2}\frac{y_{2}}{t}} + \frac{P_{2}}{y_{2}}} = {f_{2}(t)}},$

where y₁ and y₂ are the radii of sister branches of bronchioles relativeto an offset y_(o) . For example, the bronchioles may be between thefourth and eighth bronchial bifurcations. One form of coupling isthrough the fact that a flow f(t) through the parent bronchiole ofbronchioles 1 and 2 is f(t)=f₁(t)+f₂(t), so that if one sisterbronchiole constricts and the other sister bronchiole does not, the flowf(t) will be preferentially distributed to the latter bronchiole. Forpurposes of estimating the flows, it is assumed that nasal and/or oralairflow is measured (e.g., with thermistors) in conjunction withrespiratory inductive plethysmography, mercury in silastic strain gaugesor impedance pneumography so as to measure total respiratory air flow,which can be calibration with a spirometer. Assuming that the lengths ofthe bronchi and bronchioles are the same at any corresponding level ofbranching, assuming the validity of Ohm's law and Poiseuille's law, andgiven the measured total air flow, the values of the driving flows f₁(t)and f₂(t) can be estimated for the current values of y₁ and y₂. Similarequations are written for the multiple levels of bronchiolebifurcations. Because flow at one level of bronchiole branching caninfluence flow that is connected to it at another level, the equationsfor the bronchiole oscillators are therefore coupled to one another atleast by virtue of the anatomy of the lung and flow within the branchingbronchioles.

According to the invention, the presence of irritant in the airstream ofany bronchiole (or other trigger surrogate) is accounted for by makingparameters describing the potential P be a function of the flow andconcentration of environmental irritant. For example, with theasymmetric potential

${P = {{\frac{b}{2}y^{2}} + {\frac{a}{4}y^{4}} + {y\left\lbrack {c + {{df}(t)}} \right\rbrack}}},$

where d is a parameter that is a function of irritant concentration, thesystem would preferentially constrict the bronchiole on inspiration(positive f, preventing the irritant from reaching the alveoli) andpreferentially dilate the bronchiole on expiration (negative f, allowingthe irritant to be expelled from the alveoli). If K is the irritantconcentration, then for example, the dependence of parameter d on K maybe expressed as d=d₀+d₁K+d₂K²+ . . . .

An increase in the parameter c would increase the stability of thepotential well corresponding to bronchoconstriction, independently ofany changes in the flow. Accordingly, stimulation of the bronchioles byhistamine, the parasympathetic nervous system, or any other factor thatpromotes bronchoconstriction should be accompanied by an increase in theparameter c. Conversely, a decrease in the parameter c would increasethe stability of the potential well corresponding to bronchodilation.Accordingly, stimulation of the bronchioles by epinephrine, thesympathetic nervous system, or any other factor that promotesbronchodilation should be accompanied by a decrease in the parameter c.For example, one may write c as c=c_(c)−c_(d), where an increase inc_(c) caused bronchoconstriction and an increase in c_(d) causesbronchodilation. Then, the vagal nerve stimulation S(t), which wasdefined above, may be introduced through the parameter c_(d). Forexample, c_(d)=C_(d0)+C_(d1) S+C_(d2) S²+ . . . .

Breathing is to some extent under voluntary control, so that anindividual can deliberately vary the driving function f(t). On the otherhand, breathing is also to some extent involuntary and controlled by thenervous system. Accordingly, one may expand the above model to accountfor respiratory reflexes [H. T. MILHORN Jr., R. Benton, R. Ross, and A.C. Guyton. A mathematical model of the human respiratory control system.Biophys J. 5(1965):27-46]. To do so, the coupling parameter(s) may alsobe made to be a function of multiple oscillator values, possibly at aprevious time t-A, so as to account for the time delay A in neuralreflexes between afferent signals and efferent effects that coupleoscillators to one another. Such an expanded neural control model may beused to forecast f(t), or alternatively, non-physiological models may beused to forecast future values of f(t) based on previous values of f(t)[CAMINAL P, Domingo L, Giraldo B F, Vallverdú M, Benito S, Vazquez G,Kaplan D. Variability analysis of the respiratory volume based onnon-linear prediction methods. Med Biol Eng Comput 42(1, 2004):86-91].It is understood that additional extensions of the above dynamical modelmay make the anatomy and physiology more complete, accurate or detailed;for example, one may wish to create a more realistic model of thepatient's lung anatomy than what was described above [LEE, S. L. A.;Kouzani, A. Z.; Hu, E.J.; From lung images to lung models: A review.IEEE International Joint Conference on Neural Networks 2008: 2377-2383].

Usefulness of this method is dependent on the extent to which thepatient is willing to undergo measurement to allow estimation of anembodiment of the equations' parameters. It is understood that themeasurement will consist of a period of baseline monitoring, followed bya period during which the vagus nerve is stimulated using a defaultstimulation protocol or during which vagal nerve stimulation parametersare varied. The most useful measurements would be ones in which nearbygroups of bronchioles are measured separately, so as to be able toestimate parameters separately for those localized groups ofoscillators. This will require imaging of the lung in order to evaluatethe spatial heterogeneity of bronchiolar constriction.

Many methods exist for the noninvasive imaging of the lung. However, thenoninvasive imaging methods that are preferred here are those that maybe performed by continuous noninvasive ambulatory monitoring. At thepresent time, the preferred imaging methods comprise electricalimpedance tomography and acoustic imaging. Electrical impedancetomography (EIT) is an imaging technique in which an image of theconductivity of the chest is inferred from surface electricalmeasurements. To perform EIT, conducting electrodes are attached to theskin of the patient and small alternating currents are applied to someor all of the electrodes. The resulting electrical potentials aremeasured, and the process may be repeated for numerous differentconfigurations of applied current. A calculation is then performed toinfer the lung structure that could have given rise to the measuredelectrical potentials [David HOLDER. Electrical impedance tomography:methods, history, and applications. Institute of Physics Publishing,Bristol and Philadelphia, 2005; WENG TR, Spence JA, Polgar G, Nyboer J.Measurement of regional lung function by tetrapolar electrical impedanceplethysmography. Chest 76(1,1979):64-9; FRERICHS I. Electrical impedancetomography (EIT) in applications related to lung and ventilation: areview of experimental and clinical activities. Physiol Meas.21(2,2002):R1-21; FRERICHS I, Hinz J, Herrmann P, Weisser G, Hahn G,Dudykevych T, Quintel M, Hellige G. Detection of local lung air contentby electrical impedance tomography compared with electron beam CT. JAppl Physiol 93(2,2002):660-6; J. KARSTEN, T. Meier, H. Heinze.Bedside-measurements of electrical impedance tomography and functionalresidual capacity during positioning therapy in a case of acuterespiratory failure Applied Cardiopulmonary Pathophysiology, 15(2011):81-86; FAGERBERG A, Sondergaard S, Karason S, Aneman A. Electricalimpedance tomography and heterogeneity of pulmonary perfusion andventilation in porcine acute lung injury. Acta Anaesthesiol Scand. 2009November; 53(10):1300-9].

The other noninvasive ambulatory imaging method, acoustic imaging,involves the placement of multiple microphones on the patient's chestand back. It is particularly useful to detect and localize groups ofbronchioles that have abruptly opened and made a corresponding sound[KOMPIS M, Pasterkamp H, Wodicka GR. Acoustic imaging of the humanchest. Chest 120(4,2001):1309-21; PASTERKAMP H, Kraman S S, Wodicka G R.Respiratory sounds. Advances beyond the stethoscope. Am J Respir CritCare Med 156(3 Pt 1,1997):974-87; Adriano M. ALCENAR, Arnab Majumdar,Zoltan Hantos, Sergey V. Buldyrev, H. Eugene Stanley, Bela Suki.Crackles and instabilities during lung inflation. Physica A 357(1,2005):18-26].

In addition to these noninvasive measurements, as well as conventionalambulatory measurements for breathing, heart rate and its variability,electrodermal activity, and the like, one would preferably use anaccelerometer and/or inclinometer so as to account for changes in lunganatomy and physiology as the patient changes posture or moves about[GALVIN I, Drummond G B, Nirmalan M. Distribution of blood flow andventilation in the lung: gravity is not the only factor. Br J Anaesth98(4,2007):420-8]. The sensors may be embedded in garments or placed insports wristwatches, as currently used in programs that monitor thephysiological status of soldiers [G. A. Shaw, A. M. Siegel, G. Zogbi,and T. P. Opar. Warfighter physiological and environmental monitoring: astudy for the U.S. Army Research Institute in Environmental Medicine andthe Soldier Systems Center. MIT Lincoln Laboratory, Lexington Mass. 1Nov. 2004, pp. 1-141].

Estimation of parameters of the equations from continuously acquireddata may be made using existing methods such as the multiple shootingand recursive (e.g., Kalman filter) approaches [Henning

U. VOSS and Jens Timmer. Nonlinear dynamical system identification fromuncertain and indirect measurements. International Journal ofBifurcation and Chaos 14(6,2004):1905-1933], or synchronization methods[H D I ABARBANEL, D R Creveling, and J M Jeanne. Estimation ofparameters in nonlinear systems using balanced synchronization. PhysicalReview E 77(2008):016208, pp 1-14]. As the patient's ambulatory dataevolve in time, the estimated parameters may also evolve in time andmust be updated.

After parameter estimation, numerical simulation with thecoupled-oscillator equations into the future may forecast the imminentonset of an asthma attack, i.e., an abrupt transition wherein groups ofbronchioles constrict (see FIG. 9). It is understood that the simulationmust occur at a rate that is significantly faster than actual time,otherwise there would be little warning for the patient. When such awarning is given, the patient or a caregiver would perform vagus nervestimulation as described above in order to avert the asthma attack.

For situations in which it is impractical to use the above gray-boxmodel of asthma, for example, if the patient is unwilling to wear theelectrical impedance tomography and acoustic imaging sensors formeasuring respiratory heterogeneity, then one may instead use theblack-box approach that was described above (and also below inconnection with migraine, strokes, and panic attacks) using theremaining sensors (respiration, environmental sensors, etc.) [G. A.Shaw, A. M. Siegel, G. Zogbi, and T. P. Opar. Warfighter physiologicaland environmental monitoring: a study for the U.S. Army ResearchInstitute in Environmental Medicine and the Soldier Systems Center. MITLincoln Laboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. In thatcase, the patient would mark the onset of an asthma attack with an eventbutton, and the set of ambulatory measurements would be used to train asupport vector machine classifier model. After training, that model willbe used to forecast the asthma attack and advise the patient to performvagus nerve stimulation.

Methods for Averting Imminent Epilepsy Seizures

There is a large literature on methods for forecasting epilepsyseizures. Current methods have been the subject of several reviews[Brian LITT and Javier Echauz. Prediction of epileptic seizures. LancetNeurology 1(2002): 22-30; MORMANN F, Andrzejak R G, Elger C E, LehnertzK. Seizure prediction: the long and winding road. Brain 130(Pt2,2007):314-33; MORMANN F, Kreuz T, Rieke C, Andrzejak R G, Kraskov A,David P, Elger C E, Lehnertz K. On the predictability of epilepticseizures. Clin Neurophysiol 116(3,2005):569-87; MORMANN F, Elger C E,Lehnertz K. Seizure anticipation: from algorithms to clinical practice.Curr Opin Neurol 19(2,2006):187-93]. Tools are also available for thedevelopment of new methods for forecasting epilepsy seizures [TEIXEIRA CA, Direito B, Feldwisch-Drentrup H, Valderrama M, Costa R P,Alvarado-Rojas C, Nikolopoulos S, Le Van Quyen M, Timmer J, Schelter B,Dourado A. EPILAB: a software package for studies on the prediction ofepileptic seizures. J Neurosci Methods. 200(2,2011): 257-71].

The brain-wave data used to make the forecast are either from electrodesthat are implanted in the patient's brain, or fromelectroencephalographic electrodes that are worn or attached to thepatient's scalp [CASSON A, Yates D, Smith S, Duncan J,Rodriguez-Villegas E. Wearable electroencephalography. What is it, whyis it needed, and what does it entail? IEEE Eng Med Biol Mag.29(3,2010):44-56]. Additional data may also be useful in making theforecast, such as data concerning heart rate [DELAMONT R S, Julu P O,Jamal G A. Changes in a measure of cardiac vagal activity before andafter epileptic seizures. Epilepsy Res 35(2,1999):87-94]. Thus,VALDERRAMA et al. are able to improve the forecast of a seizure byincluding the analysis of ECG data with EEG data [M. VALDERRAMA, S.Nikolopoulos, C. Adam, Vincent Navarro and M. Le Van Quyen.Patient-specific seizure prediction using a multi-feature andmulti-modal EEG-ECG classification. XII Mediterranean Conference onMedical and Biological Engineering and Computing 2010, IFMBEProceedings, 2010, Volume 29, Part 1, 77-80]. In fact, OSORIO andSchachter suggest that seizures may be detected using only ECG-deriveddata, following electrographic onset, but before clinical onset, of theseizure [I. OSORIO, S. Schachter. Extracerebral detection of seizures: Anew era in epileptology? Epilepsy & Behavior 22 (2011): S82-S87]. Lackof sleep and the patient's self-prediction of whether a seizure isimminent may also useful in making a forecast [HAUT S R, Hall C B, MasurJ, Lipton R B. Seizure occurrence: precipitants and prediction.Neurology. 69(20,2007):1905-10]. Furthermore, accelerometer data may beuseful for forecasting seizures, when used in conjunction withelectrodermal sensor measurements [Ming-Zher P O H, Tobias Loddenkemper,Claus Reinsberger, Nicholas C. Swenson, Shubhi Goyal, Mangwe C. Sabtala,Joseph R. Madsen, and Rosalind W. Picard. Convulsive seizure detectionusing a wrist-worn electrodermal activity and accelerometry biosensor.Epilepsia 53(5,2012):e93-e97]. Motion data collected using anaccelerometer may be useful for detecting artifacts [Sweeney K T, LeamyD J, Ward T E, McLoone S. Intelligent artifact classification forambulatory physiological signals. Conf Proc IEEE Eng Med Biol Soc. 2010;2010:6349-52].

Proposed countermeasures against the forecasted epileptic seizurescomprise: on-demand excretion of fast-acting anticonvulsant substances,local cooling, biofeedback operant conditioning, and electrical or otherstimulation to reset brain dynamics to a state that will not developinto a seizure [STACEY W C, Litt B. Technology insight: neuroengineeringand epilepsy-designing devices for seizure control. Nat Clin PractNeurol 4(4,2008):190-201].The electrical stimulation countermeasuresthat have been proposed involved deep-brain stimulation or other uses ofimplanted electrodes, including implanted vagus nerve stimulators, butnot non-invasive vagal nerve stimulation. Non-invasive magneticstimulation has also been proposed, but not of the vagus nerve.[THEODORE W H, Fisher R. Brain stimulation for epilepsy. Acta NeurochirSuppl. 97(2,2007):261-72]. Most electrical stimulation countermeasuresinvolve open-loop devices, meaning that there is no direct feedback tothe electrical stimulator from sensors that can be used to forecast ormonitor the epileptic seizure. More recently, closed-loop stimulatorshave also been described wherein there may be feedback to the electricalstimulator from the sensors. Closed-loop therapy has the potentialadvantage that it may be precisely timed or dosed to be administeredonly when and where needed, for example, administered immediately uponor before seizure detection, directly to the site of seizure origin andwith variable dose depending upon detected seizure characteristics[Patents U.S. Pat. No. 6,480,743, entitled System and method foradaptive brain stimulation, to Kirkpatrick et al; U.S. Pat. No.7,231,254, entitled Closed-loop feedback-driven neuromodulation, toDiLorenzo; U.S. Pat. No. 7,209,787, entitled Apparatus and method forclosed-loop intracranial stimulation for optimal control of neurologicaldisease, to DiLorenzo].

It should be noted that some patients are able to predict their ownepileptic seizures well in advance, and some are able to do so reliably[HAUT S R, Hall C B, LeValley A J, Lipton R B. Can patients withepilepsy predict their seizures? Neurology. 68(4,2007):262-6; STACEY WC, Litt B. Technology insight: neuroengineering and epilepsy-designingdevices for seizure control. Nat Clin Pract Neurol 4(4,2008):190-201].Accordingly, one aspect of the present invention comprises the steps of(1) a patient predicts his/her own epileptic seizure, or a devicepredicts the seizure using data obtained from EEG devices plus accessorynoninvasive data (e.g., heart rate, electrodermal sensors, and motion),as described in publications such as the ones cited above; and (2) thepatient or a caregiver performs noninvasive vagal nerve stimulationusing devices that are disclosed herein. The rationale for performingthe vagal nerve stimulation is that it is already an adjunctive therapyfor pharmaco-resistant partial epilepsy, having been approved since 1997by the FDA. This includes the use of vagal nerve stimulation performedon-demand by the epileptic patient [BOON, P., Vonck, K., Van Walleghem,P., D′Have, M., Goossens, L., Vandekerckhove, T., Caemaert, J., DeReuck, J., Programmed and magnet-induced vagus nerve stimulation forrefractory epilepsy. J. Clin. Neurophysiol. 18(2001):402-407; MORRISIII, G. L., 2003. A retrospective analysis of the effects ofmagnet-activated stimulation in conjunction with vagus nerve stimulationtherapy. Epilepsy Behay. 4(2003): 740-745]. A novelty of the presentdisclosure is that the vagus nerve stimulation is performednoninvasively and in anticipation of an imminent attack. Furthermore, anovel “closed-loop” strategy for selecting the parameters in FIG. 2 wasdisclosed above in connection with tuning of a controller, in whichseveral alternate sets of stimulator values are available for use.

Methods for Averting Imminent Migraine Headaches

The pathophysiology of migraine and other sudden-onset headaches wasdescribed in the co-pending, commonly assigned application no.13/109,250 filed May 17, 2011 entitiled ELECTRICAL AND MAGNETICSTIMULATORS USED TO TREAT MIGRAINE/SINUS HEADACHE AND COMORBIDDISORDERS. As described there, migraine attacks are often thought to betriggered by environmental, physiological, and/or cognitive sets ofevents. The patient may also need to be in a permissive physical andmental state for the trigger to be effective. Thus, the migraine may betriggered by a situation or thought, but a physiologically measurablepermissive state that is detectable shortly before the attack may alsobe required, and detection of that permissive state may be used toforecast that an attack is imminent. Triggers for migraine attacks (alsocalled precipitating factors) were described in the above-citedcommonly-assigned patent application and comprise: stress and negativeemotions; hormonal factors for females (menstruation, menopause,pregnancy, use of oral contraceptives, and hormone replacement therapy);flicker, glare and eyestrain; noise; odors (exhaust fumes, cleaningsolutions, perfume); hunger and thirst (skipped meals, delayed meals,fasting, dehydration, withdrawal of reactive foods and drinks,particularly caffeinated); consumption of certain foods (e.g.,chocolate, monosodium glutamate, pungent foods) and alcohol; weather(cold, heat, high humidity, sudden changes in weather, allergens such aspollen); fatigue; and lack of sleep or too much sleep, some of which canbe monitored using available sensors [Burstein R, Jakubowski M. Aunitary hypothesis for multiple triggers of the pain and strain ofmigraine. J Comp Neurol 493(2005):9-14; Vincent T. Martin, Michael M.Behbehani. Towards a rational understanding of migraine trigger factors.Medical Clinics of North America 85(4,2001): 911-41].

An objective of the present invention is to forecast the onset of amigraine attack, wherein ambulatory sensors placed on or about thepatient are used to make the forecast. If a patient is particularlysensitive to one of the triggers listed above, then a sensor directed tothat trigger should be used. Otherwise, the most frequently citedtrigger for migraine attacks is said to be stress and negative emotions,so sensors that may detect stress are important. These include sensorsintended specifically to detect stress [VAVRINSKY, E.; Stopjakova,V.;Majer, L. Electrical biomonitoring towards mobile diagnostics ofhuman stress influence. 2nd International Symposium on Applied Sciencesin Biomedical and Communication Technologies, 2009. ISABEL 2009: 1-6;Patent U.S. Pat. No. 7,918,780, entitled Apparatus for measuring acutestress, to El-Nokaly]. More generally, traditional physiological sensorsmay be used to detect stress symptoms associated with changes in theautonomic nervous system, such as an excess of sympathetic overparasympathetic tone. These include noninvasive ambulatory recordings ofrespiration (abdominal and thoracic plethysmography), carbon dioxide(capnometry with nasual cannula), heart rate and heart rate variability(electrocardiogram leads), skin impedance (electrodermal leads),vocalization and ambient sound (microphones), light (light sensor),motion (accelerometer), external and finger temperature (thermometers),and patient-reported events (event marker button). The sensors may beembedded in garments or placed in sports wristwatches, as currently usedin programs that monitor the physiological status of soldiers [G. A.Shaw, A. M. Siegel, G. Zogbi, and T. P. Opar. Warfighter physiologicaland environmental monitoring: a study for the U.S. Army ResearchInstitute in Environmental Medicine and the Soldier Systems Center. MITLincoln Laboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141].

Because the mental state of the patient may also be an importantpredictor of an imminent migraine, sensors directed to brain monitoringmay also be useful for making a forecast. For brain monitoring,ambulatory recording may comprise ambulatory EEG sensors [Casson A,Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3,2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 Apr;80(4):043704].

Internal chemistry may also be a useful predictor of an imminentmigraine attack, particularly migraineurs who experience an aura.Sensors that measure bodily chemicals noninvasively may make use oftransdermal reverse iontophoresis [Leboulanger B, Guy R H,Delgado-Charro M B. Reverse iontophoresis for non-invasive transdermalmonitoring. Physiol Meas. 25(3,2004):R35-50]. Particular chemicals thatmay be relevant to the pathophysiology of a migraine attack and that maybe measured by transdermal reverse iontophoresis comprise potassium,glutamate, stress hormones (e.g., ACTH and/or cortisol), and glucose.

Airborne irritants that may trigger a migraine attack may also bemeasured non-invasively in real time around an ambulatory patient [KirkJ. Englehardt and John Toon. Asthma attack: Vest-based sensors monitorenvironmental exposure to help understand causes: web page (www) at theGeorgia Tech Research Institute (.gtri) of Georgia Tech (.gatech)educational domain (.edu) insubdomain:/casestudy/asthma-vest-helps-id-asthma-causes; patentapplication US20110144515 Systems and methods for providingenvironmental monitoring, to Bayer et al.; and patent U.S. Pat. No.7,119,900; entitled Pollen sensor and method, to Okumura et al]. Forphysical external irritants, the unit of irritation should be selectedaccordingly, such as temperature for cold air as an irritant.

The disclosed invention comprises forecasting an imminent migraineattack. A training set of ambulatory recordings is acquired usingsensors such as those described above. The training set will alsoinclude the measurement of the migraine attack onset itself (e.g., frompatient activated event markers). All those recordings are used toparameterize a model that predicts the imminent onset of the migraineattack. Subsequently, the model also measures the ambulatory signals,but then calculates the likelihood of an imminent attack, and warns thepatient when a migraine attack is imminent.

Many such forecasting models may be used as described above. Theycomprise autoregressive models, or those that make use of principalcomponents, Kalman filters, wavelet transforms, hidden Markov models, orartificial neural networks. The preferred forecasting model will be onethat makes use of support vector machines. In the present context, atraining set of physiological data will have been acquired that includeswhether or not the patient is experiencing a migraine attack. Thus, theclassification of the patient's state is whether or not an attack is inprogress, and the data used to make the classification consist of theremaining acquired physiological data, evaluated at Δ time units priorto the time at which the attack data are acquired. Thus, the SVM istrained to forecast the imminence of an attack Δ time units into thefuture. After training the SVM, it is implemented as part of thecontroller to sound an alarm and advise the use of vagus nervestimulation, whenever there is a forecast of an imminent attack[Sapankevych, N.and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine4(2,2009): 24-38; Press, W H; Teukolsky, S A; Vetterling, W T; Flannery,B P (2007). Section 16.5. Support Vector Machines. In: NumericalRecipes: The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press].

The patient or a caregiver then performs noninvasive vagus nervestimulation as a prophylactic countermeasure as disclosed herein, therationale for which is described more fully in the co-pending, commonlyassigned applications no. 13/109,250 filed May 17, 2012 and 13/183,721filed July 15, 2011 herein incorporated by reference in their entirety.

Methods for Averting Imminent Transient Ischemic Attacks and Strokes

Migraineurs are at a significantly increased risk for experiencingstrokes, so the prevention of migraine headaches may also decrease thelikelihood of stroke [MacCLELLAN L R, Giles W, Cole J, Wozniak M, SternB, Mitchell B D, Kittner S J. Probable migraine with visual aura andrisk of ischemic stroke: the stroke prevention in young women study.Stroke 38(9,2007):2438-45]. A stroke is the acute loss of brain functiondue to loss of normal blood supply to the brain. This can be due to thelack of blood flow (ischemia) caused by blockage due to thrombosis orarterial embolism, or to a hemorrhage. Ischemic stroke occurs in 87% ofstroke patients may be treated with thrombolytic agents (“clotbusters”). Hemorrhagic strokes occur in 13% of stroke patients and maybenefit from neurosurgery.

A transient ischemic attack (TIA) is also caused by ischemia in thebrain, spinal cord or retina. TIAs share the same underlying etiology asstrokes and produce the same symptoms, such as contralateral paralysis,sudden weakness or numbness, dimming or loss of vision, aphasia, slurredspeech and mental confusion. Unlike a stroke, the symptoms of a TIA canresolve typically within a day, whereas the symptoms from a stroke canpersist due to death of neural tissue (acute infarction) [PRABHAKARAN S.Reversible brain ischemia: lessons from transient ischemic attack. CurrOpin Neurol 20(1,2007):65-70].

Prediction that a stroke or TIA is imminent may be based upon the likelyformation of a thrombosis or arterial embolism. In that regard, thereexists an ambulatory monitoring device that will monitor for cerebralemboli [MacKINNON A D, Aaslid R, Markus H S. Long-term ambulatorymonitoring for cerebral emboli using transcranial Doppler ultrasound.Stroke 35(1,2004):73-8]. It measures the passage of emboli, typically atthe middle cerebral artery, using a transcranial Doppler signal. Whereassome cerebral emboli produce symptoms such as those listed above inconnection with the symptoms of a stroke, other emboli do not producesymptoms and may not be recognized by the patient. Therefore, in oneembodiment of the invention, the detection of an embolus with the devicementioned above is used as input for the forecasting of a TIA or stroke,but the appearance of the embolus in and of itself does not necessarilytrigger the forecast of an imminent TIA or stroke.

Risk factors for the formation of emboli include carotid stenosis andatrial fibrillation, the latter of which may start and stop inparoxsysmal atrial fibrillation. In fact, the onset of atrialfibrillation itself may be forecast as described in a following section,so the forecasting of a stroke may be considered to be an extendedversion of forecasting atrial fibrillation. In addition to these riskfactors, there are many others that are thought to predispose a patientto having a stroke or TIA. These include infection and inflammation,recreational drugs and medications, mental stress, perturbations insystemic metabolism, acute increases in blood pressure, and changes incoagulation [ELKIND M S. Why now? Moving from stroke risk factors tostroke triggers. Curr Opin Neurol 20(1,2007):51-7]. One may monitorthese risk factors noninvasively using the same ambulatory sensorsdescribed above in connection with the forecasting of migraine,including an ECG for monitoring for the presence or forecast of atrialfibrillation, ambulatory blood pressure monitors for the presence ofacute increases in blood pressure, and body temperature thermometers forthe presence of infection and inflammation. For the monitoring of drugand medications, systemic metabolism, and changes in coagulation, bodychemistry may also be measure noninvasively using transdermal reverseiontophoresis [Leboulanger B, Guy R H, Delgado-Charro M B. Reverseiontophoresis for non-invasive transdermal monitoring. Physiol Meas25(3,2004):R35-50].

The disclosed invention comprises forecasting an imminent TIA or stroke.A training set of ambulatory recordings is acquired using sensors suchas those described above, and the training set will also include themeasurement of TIA or stroke onset (e.g., from patient activated eventmarkers upon the appearance of symptoms such as sudden weakness ornumbness, dimming or loss of vision). Measurements may include those forthe passage of emboli, for example at the middle cerebral artery, usingthe transcranial Doppler ultrasound device that was described above. Thedetection of an embolus with this device is used as input for theforecasting of a TIA or stroke, but the appearance of the embolus doesnot in and of itself necessarily trigger the forecast of an imminent TIAor stroke. The set of all training measurements is then used toparameterize a model that predicts the imminent onset of the TIA orstroke. When the parameterized model is in use after training of themodel, the signals are also acquired, then the model calculates thelikelihood of an imminent stroke using the acquired data and warns thepatient when a stroke or TIA may be imminent.

Many such forecasting models may be used. They comprise autoregressivemodels or those that make use of principal components, Kalman filters,wavelet transforms, hidden Markov models, or artificial neural networks.The preferred forecasting model will be one that makes use of supportvector machines (SVM). In the present context, a training set ofphysiological data will have been acquired that includes whether or notthe patient is experiencing a stroke or TIA. Thus, the classification ofthe patient's state is whether or not a stroke is in progress, and thedata used to make the classification consist of the remaining acquiredphysiological data, evaluated at Δ time units prior to the time at whichthe stroke data are acquired. Consequently, the SVM is trained toforecast the imminence of a stroke Δ time units into the future. Aftertraining the SVM, it is implemented as part of the controller to soundan alarm and advise the use of vagal nerve stimulation, whenever thereis a forecast of an imminent stroke [Sapankevych, N. and Sankar, R. TimeSeries Prediction Using Support Vector Machines: A Survey. IEEEComputational Intelligence Magazine 4(2,2009): 24-38; Press, W H;Teukolsky, S A; Vetterling, W T; Flannery, B P (2007). Section 16.5.Support Vector Machines. In: Numerical Recipes: The Art of ScientificComputing (3rd ed.). New York: Cambridge University Press].

The patient or a caregiver then performs noninvasive vagal nervestimulation as a prophylactic countermeasure using devices and methodsdisclosed herein, the rationale for which is described more fully in thepublication: MRAVEC B. The role of the vagus nerve in stroke. AutonNeurosci 158(1-2,2010):8-12.

Methods for Averting Imminent Atrial Fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia, in which thenormal electrical impulses that are generated by the sinoatrial node ofthe heart are inundated by disorganized electrical impulses thatoriginate in the atria and pulmonary veins, leading to the conduction ofirregular impulses to the ventricles that generate the heartbeat.Individuals with AF usually have a significantly increased risk ofstroke, which increases during AF because blood may pool and form clotsin the poorly contracting atria. The risk of a stroke increases whenpatients have a previous ischemic stroke, hypertension, diabetes,congestive heart failure, and an age greater than 75 years. The riskalso increases as a function of the length of time that the atrium isfibrillating.

When atrial fibrillation self-terminates, generally within a week, it isknown as paroxsysmal atrial fibrillation. However, atrial fibrillationmay also become a persistent or permanent arrhythmia, in which casemedications, electrical cardioversion, or surgical ablation is oftenattempted in order to convert the atrial fibrillation back into a normalheart rhythm. Patients with atrial fibrillation are also often treatedwith warfarin or other anticoagulants, at which time they must follow arestricted diet. Some, but not all, patients with artial fibrillationexperience discomfort as the atrium fibrillates, especially if the heartrate is high.

A group of methods has as its goal the extraction, from a surfaceelectrocardiogram, that portion of the electrocardiogram that is due toatrial electrical activity, separated from the much larger ventricularelectrical activity. This may be accomplished, for example, byidentifying different types of QRST complexes, averaging those complexesover multiple beats, then subtracting the corresponding averaged QRSTcomplex from the electrocardiogram, so as to extract an atrialelectrocardiogram. Alternatively, methods involving principal componentanalysis may be used to extract the atrial waveform without explicitlysubtracting a ventricular waveform, or extraction may be performedduring the T-Q interval when no ventricular waveform need be subtracted[BOLLMANN A, Husser D, Mainardi L, Lombardi F, Langley P, Murray A,Rietall, Millet J, Olsson S B, Stridh M, Sornmo L. Analysis of surfaceelectrocardiograms in atrial fibrillation: techniques, research, andclinical applications. Europace 8(11,2006):911-26; STRIDH M, Bollmann A,Olsson S B, Sornmo L. Detection and feature extraction of atrialtachyarrhythmias. A three stage method of time-frequency analysis. IEEEEng Med Biol Mag 25(6,2006):31-9.; D.A. CORINO, Roberto Sassi, Luca T.Mainardi, Sergio Cerutti. Signal processing methods for informationenhancement in atrial fibrillation: spectral analysis and non-linearparameters. Biomedical Signal Processing and Control 1(4,2006):271-281;Mathieu LEMAY. Data processing techniques for the characterization ofatrial fibrillation. 2007 thesis. Ecole Polytechnique Federale deLausanne. Lausanne, Switzerland. pp. 1-134; R SASSl, VDA Corino, LTMainardi. Analysis of surface atrial signals using spectral methods fortime series with missing data. Computers in Cardiology 34(2007):153-156;SORNMO L, Stridh M, Husser D, Bollmann A, Olsson S B. Analysis of atrialfibrillation: from electrocardiogram signal processing to clinicalmanagement. Philosophical Transactions. Series A, Mathematical,Physical, and Engineering Sciences 367(1887,2009): 235-53; ABACHERLI R,Leber R, Lemay M, Vesin JM, van Oosterom A, Schmid H J, Kappenberger L.Development of a toolbox for electrocardiogram-based interpretation ofatrial fibrillation. J Electrocardiol 42(6,2009):517-21]. Once anextracted atrial electrocardiogram is available, possibly correspondingpreferentially to one or more selected regions of the atria, thecardiogram may then be analyzed in order to partially characterize thepatient's AF. For example, construction of the Fourier transform of theatrial electrocardiogram reveals that many patients have single,narrow-banded fibrillatory frequency spectra, with a fibrillatory ratethat varies greatly between individuals (typically in the range 4 to 9Hz). Transforms other than the Fourier transform may also be used[CIACCIO E J, Biviano A B, Whang W, Coromilas J, Garan H. A newtransform for the analysis of complex fractionated atrial electrograms.Biomed Eng Online 10(2011):35].

Atrial fibrillation is a type of bistable state. Once the atrialfibrillation starts, it may be difficult to cardiovert it back intonormal sinus rhythm. On the other hand, if a patient is currently innormal sinus rhythm, it may take a triggering event or circumstance tomake the transition into atrial fibrillation. Thus, the pathophysiologyof atrial fibrillation consists of both a triggering focal activator andchanges in the atrial electrophysiologic properties capable ofmaintaining AF. Accordingly, one strategy for managing patients who areat risk of transitioning to atrial fibrillation from normal sinus rhythmis to predict that the onset of AF is imminent, and then used acountermeasure to avert the AF. The countermeasure might be one used totreat atrial fibrillation that is in progress, such as theadministration of a beta blocker or calcium channel blocker drug.

According to the present invention, a preferred countermeasure comprisesthe administration of low level vagus nerve stimulation. One rationalefor performing vagus nerve stimulation is that transient changes invagal outflow are temporally related to the onset of AF [Vikman S,Lindgren K, Makikallio T H, Yli-Mayry S, Airaksinen K E, Huikuri H V.Heart rate turbulence after atrial premature beats before spontaneousonset of atrial fibrillation. J Am Coll Cardiol. 45(2,2005):278-84]. Atone time, stimulation of the vagus nerve was considered to exacerbaterather than ameliorate the dangers of AF, but this is no longer thecase, provided that parameters of the vagal nerve stimulation areproperly selected [ZHANG Y, Mazgalev TN. Arrhythmias and vagus nervestimulation. Heart Fail Rev 16(2,2011):147-61; ZHANG Y, IIsar I, SabbahH N, Ben David T, Mazgalev T N. Relationship between right cervicalvagus nerve stimulation and atrial fibrillation inducibility:therapeutic intensities do not increase arrhythmogenesis. HeartRhythm.6(2,2009):244-50].

For the present invention, a black-box model may be used to make theforecast of imminent AF, and the preferred model will be one that makesuse of support vector machines. A support vector machine (SVM) is analgorithmic approach to the problem of classification within the largercontext of supervised learning. In the present context, a training setof physiological data will have been acquired that includes whether ornot the patient is experiencing AF. Thus, the classification of thepatient's state is whether or not the AF is in progress, and the dataused to make the classification consist of the remaining acquiredphysiological data (ECG, along with simultaneous data from other sensorssuch as for respiration and accelerometry for motion artifact), as wellas parameters of the stimulator device (if it is currently being used ona patient in AF), evaluated at Δ time units prior to the time at whichthe binary AF (yes/no) data are acquired. Thus, for a patient who is inAF, the SVM is trained to forecast the termination of AF, Δ time unitsinto the future, and the training set includes the time-course offeatures extracted from the ECG, including the atrial fibrillatorywaveform and features extracted from it, such as the dominant peakfrequency and its width. For a patient who is not in AF, the SVM istrained to forecast the imminence of AF, Δ time units into the future,and the training set includes the time-course of features extracted fromthe ECG, including heart rate variability indices of autonomic balance,P-wave duration and morphology, and the frequency of atrial prematurebeats. After training the SVM, it is implemented as part of thecontroller. For patients in normal sinus rhythm, the controller maysound an alarm and advise the use of vagal nerve stimulation, wheneverthere is a forecast of imminent AF [Sapankevych, N.and Sankar, R. TimeSeries Prediction Using Support Vector Machines: A Survey. IEEEComputational Intelligence Magazine 4(2,2009): 24-38; Press, W H;Teukolsky, S A; Vetterling, W T; Flannery, B P (2007). Section 16.5.Support Vector Machines. In: Numerical Recipes: The Art of ScientificComputing (3rd ed.). New York: Cambridge University Press].

Several other methods have been proposed to predict the imminent onsetof atrial fibrillation in a patient who is currently in sinus rhythm [GBMOODY, AL Goldberger, S McClennen, SP Swiryn. Predicting the onset ofparoxysmal atrial fibrillation: the Computers in Cardiology Challenge2001. Computers in Cardiology 28(2001):113-116]. Note that predictionsaccording to the present invention may be better than previous ones,because they may be based on the analysis of many simultaneousphysiological signals, as described in the BACKGROUND OF THE INVENTIONsection of this disclosure. At a minimum, the prediction is made from ananalysis of an electrocardiogram of the patient over an extended periodof time, which requires the patient to have attached monitoring devicesor wear them in sports watches or special clothing, even though thepatient is not necessarily wearing the vagal nerve stimulator.Measurement of respiration using noninvasive inductive plethysmography,mercury in silastic strain gauges or impedance pneumography is alsoadvised, in order to account for the effects of respiration on the heartrate. A noninvasive accelerometer may also be included among theambulatory sensors in order to account for motion artifacts, andalthough AF can be detected from the ECG alone, an event marker may alsobe included in order for the patient to mark relevant circumstances andsensations.

Many onset-of-AF prediction methods involve an analysis of heart ratevariability, particularly the high frequency component of heart ratevariability as an indicator of vagal tone [VIKMAN S, Makikallio T H,Yli-Mayry S, Pikkujamsa S, Koivisto A M, Reinikainen P, Airaksinen K E,Huikuri H V. Altered complexity and correlation properties of R-Rinterval dynamics before the spontaneous onset of paroxysmal atrialfibrillation. Circulation 100(20,1999):2079-84; FIORANELLI M, Piccoli M,Mileto GM, Sgreccia F, Azzolini P, Risa MP, Francardelli RL, VenturiniE, Puglisi A. Analysis of heart rate variability five minutes before theonset of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol22(5,1999):743-9; BETTONI M, Zimmermann M. Autonomic tone variationsbefore the onset of paroxysmal atrial fibrillation. Circulation105(23,2002):2753-9; VIKMAN S, Lindgren K, Mäkikallio T H, Yli-Mayry S,Airaksinen KE, Huikuri HV. Heart rate turbulence after atrial prematurebeats before spontaneous onset of atrial fibrillation. J Am CollCardiol. 45(2,2005):278-84; SUGIURA H, Chinushi M, Komura S, Hirono T,Aizawa Y. Heart rate variability is a useful parameter for evaluation ofanticholinergic effect associated with inducibility of atrialfibrillation. Pacing Clin Electrophysiol 28(11,2005):1208-14]. PatentU.S. Pat. No. 5,749,900, entitled Implantable medical device responsiveto heart rate variability analysis, to Schroeppel et al, describeinvasive methods for forecasting and responding to cardiac events, butdoes not mention atrial fibrillation. Some onset-of-AF predictionmethods evaluate rates of atrial and ventricular depolarization [Patentapplication US20040148109, entitled Method and apparatus for predictionof cardiac dysfunction, to Fischer], and others take into account theeffects of circadian rhythm on the onset of AF [Patent applicationUS20100145208, entitled Device For Predicting Tachyarrhythmias And/OrAtrial Arrhythmias, to Schirdewan].

Before the onset of atrial fibrillation, the frequency of atrialpremature beats also increases, and the dispersion and morphology of thecorresponding P-waves change [HAYN D, Kollmann A, Schreier

G. Predicting initiation and termination of atrial fibrillation from theECG. Biomed Tech 52(1,2007):5-10; VINCENTL A, Brambilla R, Fumagalli MG,Merola R, Pedretti S. Onset mechanism of paroxysmal atrial fibrillationdetected by ambulatory Holter monitoring. Europace 8(3,2006):204-10;MAGNANI JW, Williamson M A, Ellinor P T, Monahan K M, Benjamin E J. Pwave indices: current status and future directions in epidemiology,clinical, and research applications. Circ Arrhythm Electrophysiol2(1,2009):72-9]. In regards validation of P-wave analysis algorithms, itis understood that P-wave changes can be measured with the aid ofultrasound more accurately than from the ECG alone [MERCKX K L, De Vos CB, Palmans A, Habets, J Cheriex E C, Crijns Hi, Tieleman R G. Atrialactivation time determined by transthoracic Doppler tissue imaging canbe used as an estimate of the total duration of atrial electricalactivation. J Am Soc Echocardiogr. 18(9,2005):940-4; DEVOS C B, Weijs B,Crijns Hi, Cheriex E C, Palmans A, Habets J, Prins MH, Pisters R,Nieuwlaat R, Tieleman R G. Atrial tissue Doppler imaging for predictionof new-onset atrial fibrillation. Heart 95(10,2009):835-40].

If the patient in normal sinus rhythm has been previously treated withthe stimulator while in AF, parameters of the prophylactic stimulationmay be set to their previously effective values. Otherwise, thestimulation parameters may be set to values that are motivated bymeasurements of characteristics of the patient's heart-rate variability,P-waves, or atrial premature beat frequency. According to theabove-cited methods, the forecast of imminent AF may be triggeredbecause sympathetic versus parasympathetic tone is unbalanced, asevidenced by analysis of heart rate variability, which involves themeasurement of low versus high frequency components of the Fouriertransform of heart rate, as determined from measured R-R intervals[e.g., BETTONI M, Zimmermann M. Autonomic tone variations before theonset of paroxysmal atrial fibrillation. Circulation105(23,2002):2753-9]. Measurement of electrodermal activity may also beuseful in that regard as an indication of sympathetic activity. Theforecast of imminent AF may also be triggered because the frequency ofatrial premature beats also increases, and/or the dispersion andmorphology of the corresponding P-waves change [e.g., HAYN D, KollmannA, Schreier G. Predicting initiation and termination of atrialfibrillation from the ECG. Biomed Tech 52(1,2007):5-10]. Normal(setpoint) values for indices concerning the balance of sympathetic andparasympathetic tone, atrial premature beat frequency, and P-wavemorphology and duration may be assumed from values found in theliterature, or they may be measured for each patient while the patientis in normal sinus rhythm. The controller with vagus nerve stimulatorattached may be tuned by preliminarily stimulating the patient todetermine the effect that the stimulation has on the values of thoseindices, for given sets of stimulator parameter values. Such indiceswill normally fluctuate, so after tuning, the stimulator may then beused to continuously and automatically stimulate the patient to minimizethe error between the fluctuating index values and their setpoints. Theinvention contemplates that such feedback control could involvevariation in any of the stimulator's parameters, including the amplitudeof the stimulation signal, although the maximum allowed amplitude wouldgenerally be constrained not to decrease the heart rate of an individualin normal sinus rhythm.

However, in a preferred embodiment of the invention for averting AF, thenerve stimulator would not be used continuously to maintain thefluctuating index values to within a range about the setpoints. Instead,the patient would not continuously wear the vagus nerve stimulator, butwould use the vagus nerve stimulator only when imminent AF wasforecasted during continuous monitoring of the patient's physiologicalsignals by the controller. After the controller sounds the alarm, thepatient or a caregiver would then apply the vagus nerve stimulator tothe patient's neck, using stimulation parameters that had already beenselected by tuning the controller, as described above. The stimulationwould then be maintained until the controller no longer forecastsimminent AF, or until the physiological indices were within acceptablelimits, or until a predetermined session-duration has elapsed.

A different strategy for selecting the stimulator's parameters may alsobe used, in which several alternate sets of stimulator values areavailable for use. This strategy would be used when properties of thepatient's normal P-wave, heart rate variability, and atrial prematurebeat frequency indices are not stationary. For example, the normal indexvalues may at one time have certain normal semi-stationarycharacteristics, but at a later time, they may have differentsemi-stationary characteristics, for example because of circadianrhythms. In each epoch, the controller may be tuned in accordance withthe normal P-wave morphology, heart rate variability, and atrialpremature beat frequency indices that characterize that epoch. Defaultstimulation parameter values may be different, depending on whichsemi-stationary epoch obtained at the time of controller tuning.Accordingly, when the stimulator is eventually used for prophylactictreatment of a patient, the stimulator should be set to parameter valuesthat are selected to correspond to the semi-stationary epoch thatobtains immediately before stimulation is used for the prophylactictherapy.

Therefore, one embodiment of the present invention comprises thefollowing steps: (1) a device predicts the imminent onset of atrialfibrillation using data obtained from the electrocardiogram plusaccessory noninvasive data (e.g., respiration and motion), for example,as described in publications such as the ones cited above or by using asupport vector machine model; and (2) the patient or a caregiverperforms noninvasive vagal nerve stimulation using devices that aredisclosed herein. Novelty of the present disclosure comprises the factthat the vagal nerve stimulation is performed noninvasively and inanticipation of forecasted imminent AF. The stimulation protocolcomprises low-level right-side or both-side vagal stimulation, as theprophylactic countermeasure.

Methods for Averting Imminent Myocardial Infarction

Myocardial infarction (a heart attack), is the interruption of bloodsupply and oxygen to a part of the heart, resulting in heart muscledeath (infarction). It is most commonly due to blockage of a coronaryartery, by a thrombus following the rupture of a vulnerableatherosclerotic plaque, which is an unstable collection of lipids andwhite blood cells (particularly macrophages) in the wall of an artery.In order to predict that a myocardial infarction is imminent, it istherefore necessary to determine that vulnerable atherosclerotic plaquesexist, and that their rupture is imminent [Culic V. Acute risk factorsfor myocardial infarction. Int J Cardiol 117(2,2007):260-9; TOFLER GH,Muller JE. Triggering of acute cardiovascular disease and potentialpreventive strategies. Circulation 114(17,2006):1863-72]. In addition,vulnerability to thrombosis and vulnerability of the myocardium toarrhythmia needs to be assessed [NAGHAVI M et al. From vulnerable plaqueto vulnerable patient: a call for new definitions and risk assessmentstrategies: Part II. Circulation 108(15,2003):1772-8]. In that regard,WONG describes a device that attributes the risk of myocardialinfarction to a heart rate at which angina has previously beenexperienced [Patent application US20100081951, entitled Device foridentifying the likelihood of a patient suffering a myocardialinfarction, to WONG].

The detection of various biomarkers may be used to determine theprogression of atherosclerotic plaque vulnerability and rupture,comprising: endothelial dependent vasodilation (FMD) for endothelialdysfunction; adhesion molecules for endothelial activation; macrophagesfor inflammation; MM Ps and cathepsin for proteolysis and apoptosis;lipid core fibrous cap; alphaV-beta3 integrin for angiogenesis; andfibrin, platelets, and tissue factor for thrombosis [SHAH P K.Mechanisms of plaque vulnerability and rupture. J Am Coll Cardiol 41(4Suppl S, 2003):155-225; VIRMANI R, Kolodgie F D, Burke A P, Finn A V,Gold H K, Tulenko T N, Wrenn S P, Narula J. Atherosclerotic plaqueprogression and vulnerability to rupture: angiogenesis as a source ofintraplaque hemorrhage. Arterioscler Thromb Vasc Biol25(10,2005):2054-61; CHAN D, Ng L L. Biomarkers in acute myocardialinfarction. BMC Med 8(2010):34. pp 1-11].

Several noninvasive imaging methods exist for detecting and evaluatingvulnerable coronary plaques, but currently, most of those methods arenot well suited to ambulatory monitoring [Jan G. KIPS, Patrick Segers,Luc M. Van Bortel. Identification of the vulnerable plaque: a review ofinvasive and non-invasive imaging modalities. Artery Research2(2008):21-34; BRAUNWALD E. Noninvasive detection of vulnerable coronaryplaques: Locking the barn door before the horse is stolen. J Am CollCardiol 54(1,2009):58-9].

However, noninvasive ambulatory detection of molecules involved inatherogenesis, plaque progression and vulnerability, and thrombosis canbe accomplished by using radioactive tracers that accumulate in plaqueswithin the heart [VALLABHAJOSULA S, Fuster V. Atherosclerosis: imagingtechniques and the evolving role of nuclear medicine. J Nucl Med 1997;38: 1788-96; Manca G, Parenti G, Bellina R, Boni G, Grosso M, Bernini W,Palombo C, Paterni M, Pelosi G, Lanza M, Mazzuca N, Bianchi R, DeCaterina R. 111In platelet scintigraphy for the noninvasive detection ofcarotid plaque thrombosis. Stroke. 2001 Mar;32(3):719-27; Annovazzi A,Bonanno E, Arca M, D′Alessandria C, Marcoccia A, Spagnoli LG, Violi F,Scopinaro F, De Toma G, Signore A. 99mTc-interleukin-2 scintigraphy forthe in vivo imaging of vulnerable atherosclerotic plaques. Eur J NuclMed Mol Imaging. 2006 February; 33(2):117-26; HUBALEWSKA-DYDEJCZYK A,Stomp& T, Kalembkiewicz M, Krzanowski M, Mikolajczak R, Sowa-StaszczakA, Tabor-Ciepiela B, Karczmarczyk U, Kusnierz-Cabala B, Sulowicz W.Identification of inflamed atherosclerotic plaque using 123 I-labeledinterleukin-2 scintigraphy in high-risk peritoneal dialysis patients: apilot study. Perit Dial Int 29(5,2009):568-74].

The accumulation of those radio-labeled probes may be measured in theheart in real time, within an ambulatory patient who wears a vest havinga small nuclear detector located above the patient's heart [BROARDHURSTP, Cashin P, Crawlcy J, Raftery E, Lahiri A. Clinical validation of aminiature nuclear probe system for continuous on-line monitoring ofcardiac function and ST-segment. J Nucl Med 32(1991):37-43]. Such adevice may therefore be used to predict imminent plaque rupture and asubsequent heart attack, whenever the detected radio-labeled probeexceeds a predetermined, critical measurement value. For example, thecritical value could be set based upon the experience with patients whoactually suffer a myocardial infarction when being monitored, at whichtime there will ordinarily be an abrupt change in the probe's signal.The critical value may also be based on the measurement of noninvasivesignals such as heart rate and its variability, blood pressure,respiration, electrodermal activity, and the like, wherein a preferredforecasting model would be one that makes use of support vector machinesand training sets of ambulatory data.

It is understood that at the selected critical value, the plaque mayprogress to rupture, stabilize, or even eventually regress, depending onthe presence or absence of other factors that would promote or inhibitprogression to rupture. Therefore, when the device warns the patientthat a heart attack may be imminent, the patient should (1) stop oravoid activities that may contribute to the progression to plaquerupture, such as stopping any physical activity, seek a warmerenvironment if the current environment is cold, avoid emotionallystressful situations such as driving or arguing, and have thrombolyticagents on hand as a precaution; and (2) as a prophylacticcountermeasure, the patient or a caregiver should perform noninvasivevagus nerve stimulation with a device such as those disclosed herein.

The rationale for performing vagus nerve stimulation is that it caninhibit cytokine release by inflammatory cells, promote the dilation ofa vasoconstricted blood vessel, and promote beneficial hemodynamiceffects that counteract a surge in blood pressure or heart rate, asdescribed elsewhere in this disclosure, in the co-pending, commonlyassigned applications cited in CROSS REFERENCE TO RELATED APPLICATIONS,and in TOFLER GH, Muller JE. Triggering of acute cardiovascular diseaseand potential preventive strategies. Circulation. 114(17, 2006):1863-72.

Methods for Averting Imminent Ventricular Fibrillation or VentricularTachycardia

Detecting the onset of cardiac arrhythmia, such as ventricularfibrillation and ventricular tachycardia, is a well-known physiologicalmonitoring problem for which there are many proposed solutions. Devicesthat implement a ventricular fibrillation-detection algorithm includethe wearable cardiac defibrillator vest, the implanted cardioverterdefibrillator (ICD), and devices that can act as both pacemaker anddefibrillator, including cardiac resynchronization therapy (CRT-D)devices. They may also detect the absence of ventricular fibrillation,so as to terminate the defibrillation shock once it has had its intendedeffect.

Such devices are activated to shock the patient's heart only afterfibrillation is actually detected. Devices that would shock the patientprior to ventricular fibrillation or tachycardia, in anticipation of aforecasted fibrillation event, are not used. This is presumably becausethe considerable pain that accompanies a defibrillation shock wouldcontraindicate a shock based only on a forecasted fibrillation event,which may have a significant likelihood of being a false positive.

In fact, few defibrillation algorithms even include a method forforecasting the likely onset of ventricular fibrillation, asdistinguished from only detection of ventricular fibrillation inprogress. An exception is the algorithm described by SMALL, which is notintended to be placed only in a defibrillator [Michael SMALL.Application: detecting ventricular arrhythmia. pp 69-74 In: AppliedNonlinear Time Series Analysis: Applications in Physics, Physiology andFinance. Singapore: World Scientific Series on Nonlinear Science, SeriesA, Vol. 52, 2005]. SMALL′S application is instead concerned with thebedside monitoring of cardiac patients, in which it is desired to beginthe recording and intense analysis of voluminous ECG data from apatient, but only when a fibrillation event appears to be imminent. Thealgorithm predicts imminent fibrillation when there is significant 3-6Hz content in the ECG signal as well as a signal from a nonlinearcomplexity measurement indicating that the ECG signal cannot becompressed without losing the ability to predict the timing of futureheart beats. Recording is typically triggered approximately one minutebefore the ventricular fibrillation, but the lead time may be as shortas only a few seconds.

Other such forecasting algorithms have also been described, some ofwhich are suitable for use with ambulatory measurement [MAKIKALLIO T H,Koistinen J, Jordaens L, Tulppo M P, Wood N, Golosarsky B, Peng C K,Goldberger A L, Huikuri HV. Heart rate dynamics before spontaneous onsetof ventricular fibrillation in patients with healed myocardial infarcts.Am J Cardiol 83(6,1999):880-4.; WESSEL, N. Meyerfeldt, U. Schirdewan, A.Kurths, J. Voss, A. Short-term forecasting of life-threateningarrhythmias with finite time Lyapunov exponents. Proceedings of the 20thAnnual International Conference of the IEEE Engineering in Medicine andBiology Society, 20(1,1998):326-329; Patents U.S. Pat. No. 5,437,285,entitled Method and apparatus for prediction of sudden cardiac death bysimultaneous assessment of autonomic function and cardiac electricalstability, to Verrier et al.; U.S. Pat. No. 7,822,474, entitled Methodsfor the prediction of arrhythmias and prevention of sudden cardiacdeath, to Chen; and U.S. Pat. No. 6,516,219, entitled Arrhythmiaforecasting based on morphology changes in intracardiac electrograms, toStreet; U.S. Pat. No. 5,749,900, U.S. Pat. No. 6,035,233, U.S. Pat. No.6,144,878 and U.S. Pat. No. 6,571,121, entitled Implantable medicaldevice responsive to heart rate variability analysis, to Schroeppel etal.; U.S. Pat. No. 7,822,474, entitled Methods for the prediction ofarrhythmias and prevention of sudden cardiac death, to Chen; U.S. Pat.No. 7,266,410 and U.S. Pat. No. 7,725,178, entitled Method and systemfor the prediction of cardiac arrhythmias, myocardial ischemia, andother diseased condition of the heart associated with elevatedsympathetic neural discharges, to Chen et al.; Patent applicationUS20090076339, entitled Method and device for predicting abnormalmedical events and/or assisting in diagnosis and/or monitoring,particularly in order to determine depth of anesthesia, to Quintin etal.; US20100268289, entitled Method and system for the prediction ofcardiac arrhythmias, myocardial ischemia, and other diseased conditionsof the heart associated with elevated sympathetic neural discharges, toChen et al].

For patients who do not have an implanted defibrillator, such a forecastof imminent fibrillation may be used to advise external defibrillationas a prophylactic measure, because the patient may be unable to shockhim/herself once fibrillation is in progress. However, the patient mayprefer not to do so because the forecast may be a false positive, and aprophylactic defibrillation shock would be painful and possibly unsafe.

As an alternative, the present invention discloses noninvasive vagalnerve stimulation as a prophylactic method for patients in whommonitoring algorithms, such as the one described by SMALL, predict thatventricular fibrillation or ventricular tachycardia may be imminent. Theforecast may also be based on the measurement of a more comprehensiveset of noninvasive signals such as heart rate and its variability, bloodpressure, respiration, electrodermal activity, and the like, wherein apreferred forecasting model would be one that makes use of supportvector machines and training sets of ambulatory data. The rationale forthe intervention is that vagal nerve stimulation protects againstventricular fibrillation, as described in the publications: ZHANG Y,Mazgalev TN. Arrhythmias and vagus nerve stimulation. Heart Fail Rev16(2,2011):147-61; BRACK K E, Coote J H, Ng G A. Vagus nerve stimulationprotects against ventricular fibrillation independent of muscarinicreceptor activation. Cardiovasc Res 91(3,2011):437-46]. Thus, a patientwill wear a monitor of heartrate or ECG or other physiological signals;an algorithm such as a support vector machine or the one by SMALL willuse signals from the monitoring to forecast imminent fibrillation; anaudio or other signal will be emitted by the monitoring equipmentadvising the patient or healthcare provider to perform vagus nervestimulation; and the patient will be stimulated with a noninvasivestimulator so as to avoid the forecasted arrhythmia, using a simulatorsuch as ones disclosed here.

Unlike the present invention, the above-mentioned BRACK and ZHANGpublications do not suggest the use of vagus nerve stimulation inpatients for whom imminent fibrillation is forecast. Instead, they areconcerned only with implanted stimulators and with regularly scheduledstimulation. Furthermore, the presently disclosed use of noninvasivevagal nerve stimulation could not have occurred to the authors of thosepublications, because relatively painless noninvasive vagal nervestimulators have only been disclosed in the patent applications that arecited in CROSS REFERENCE TO RELATED APPLICATIONS

Methods for Averting Imminent Panbic Attacks

MEURET reported that panic attacks may be predicted as little as 47minutes before they occur, by analyzing noninvasive ambulatoryrecordings of respiration (abdominal and thoracic plethysmography),carbon dioxide (capnometry with nasal cannula), heart rate(electrocardiogram leads), skin impedance (electrodermal leads),vocalization (microphones), light (light sensor), motion(accelerometer), external and finger temperature (thermometers), andpatient-reported events (event marker button) [MEURET AE, Rosenfield D,Wilhelm FH, Zhou E, Conrad A, Ritz T, Roth W T. Do Unexpected PanicAttacks Occur Spontaneously? Biol Psychiatry 70(10,2011):985-91]. Someattacks were cued (driving in traffic, engaged in argument) but mostwere not. Hyperventilation and increased heart rate were generally notedat times closer to the attack itself.

The disclosed invention comprises forecasting an imminent panic attackor other acute anxiety attack using ambulatory physiological recording,as was done by MUERET et al., or by using a more comprehensive set ofambulatory physiological sensors and a more powerful forecasting model,then averting the panic attack using non-invasive nerve stimulation. Forexample, preferably one also measures bodily chemicals usingnon-invasive transdermal reverse iontophoresis, particularlyelectrolytes. Thus, a training set of ambulatory recordings that includethe measurement of panic onset is used to parameterize a model thatpredicts the imminent onset of the attack. As described above, thepreferred model that is used to predict the attack is one that makes useof support vector machines. In subsequent use, the model also measuresthe ambulatory signals, calculates the likelihood of an imminent attack,and warns the patient when a panic attack is imminent. The patient or acaregiver then performs noninvasive vagal nerve stimulation as aprophylactic countermeasure as disclosed herein, the rationale for whichis described more fully in the co-pending, commonly assigned applicationSer. No. 13/109,250 filed May 17, 2011 entitled ELECTRICAL AND MAGNETICSTIMULATORS USED TO TREAT MIGRAINE/SINUS HEADACHE, RHINITIS, SINUSITIS,RHINOSINUSITIS, AND COMORBID DISORDERS. The controller with vagus nervestimulator attached may be tuned by preliminarily stimulating thepatient to determine the effect that the stimulation has on the valuesof the measured physiological signals, for given sets of stimulatorparameter values. Such indices will normally fluctuate, so after tuning,the stimulator may then be used to continuously and automaticallystimulate the patient to minimize the error between the fluctuatingphysiological variable values and their setpoints. The inventioncontemplates that such feedback control could involve variation in anyof the stimulator's parameters, including the amplitude of thestimulation signal.

Methods for Averting Imminent Depression Attacks Patent applicationUS20090292180, entitled Method and Apparatus for Analysis of Psychiatricand Physical Conditions, to MIROW, describes the use of noninvasivephysiological monitoring such as the electrocardiogram andaccelerometers (for activity measurement), with the aim of diagnosingpsychiatric and physical conditions. Although MIROW does not describe amethod for performing forecasts, she does state that “[0019] . . . .Moods and emotions, themselves the result of nonlinear brain activity,cannot be accurately forecast over long time periods, (due to their“sensitive dependence upon initial conditions”), yet short-termpredictions of mood and emotional state can be made by tracking theirspatial-temporal patterns over time. Fully nuanced mood and emotionalexpressions develop slowly in humans as they grow from infancy toadulthood. A baby exhibits abrupt discontinuous changes in mood andemotional state, whereas a healthy mature adult has modulated,appropriate moods and emotional responses to change.” Thus, whereas in achild, laughter or crying may be elicited upon experiencing a funny orsad situation or thought, in an adult, it may well be the case thatexperiencing the funny or sad situation or thought may not be enough totrigger laughing or crying. Instead, the adult may also need to be in apermissive physical and mental state for the trigger to be effective.The report by MEURET that was described above in connection with panicattacks is consistent with this view, in which the panic may betriggered by a fearful thought or situation, but a physiologicallymeasurable permissive state that is detectable shortly before the attackmay also be required, and detection of that permissive state may be usedto forecast that an attack is imminent.

In the case of depression, the depressive attack would in many casesbegin with the onset of crying. In the case of panic attacks, MUERETrelied on the patient's pressing of an event marker button to correlatethe attack with the values of ambulatory physiological or environmentalmeasurements—respiration (abdominal and thoracic plethysmography),carbon dioxide (capnometry with nasual cannula), heart rate(electrocardiogram leads), skin impedance (electrodermal leads),vocalization (microphones), light (light sensor), motion(accelerometer), external and finger temperature (thermometers). Thesame could be done to forecast the onset of a crying attack of adepressed individual, but it may not be necessary to mark the attackwith the pressing of an event button. This is because the crying, whichresults in a typical pattern of respiration, may be detected from arecorded cardio-respiratory signal and used to identify its onset andtermination [Patent application US20090048500, entitled Method for usinga non-invasive cardiac and respiratory monitoring system, to Corn].Lacrimation could also be measured noninvasively using a wetness sensorapplied to the corner of one or both eyes.

The trigeminal (fifth cranial) nerve bears the sensory pathway of thetear reflexes, and activates the facial (seventh cranial) nerve. Becausecrying is produced by lachrymal glands that are innervated byparasympathetic nerves of the seventh cranial nerve, it is thought thatcrying results from high levels of autonomic activation that might bedetected before the onset of a crying attack [GROSS A, Frederickson B L,Levenson R W. The psychophysiology of crying. Psychophysiology 31(5,1994):460-8; Ad J. J. M. VINGERHOETS, Randolph R. Cornelius, Guus L. VanHeck, Marleen C. Becht. Adult Crying: A model and review of theliterature. Review of General Psychology 4(4,2000): 354-377]. Theabove-cited article by GROSS et al measured noninvasive signals beyondthose measured by MUERET et al, and their measurement, as well asadditional ambulatory signals that are described herein, may also beuseful for forecasting a state that promotes an imminent crying attack.

The disclosed invention comprises forecasting an imminent attack as wasdone by MUERET et al using ambulatory physiological recording, exceptthat additional signals are recorded as described above, and the attackis a crying attack instead of a panic attack [MEURET A E, Rosenfield D,Wilhelm F H, Zhou E, Conrad A, Ritz T, Roth W T. Do Unexpected PanicAttacks Occur Spontaneously? Biol Psychiatry 70(10,2011):985-991]. Thus,a training set of recordings that include the measurement of crying isused to parameterize a model that predicts the imminent onset of theattack. As described above, the preferred model for making the forecastmakes use of support vector machines. Thereafter, the model alsomeasures the ambulatory signals, calculates the likelihood of animminent attack, and warns the patient when a crying attack is imminent.The patient or a caregiver then performs noninvasive vagal nervestimulation as a prophylactic countermeasure as disclosed herein, therationale for which is described more fully in the co-pending, commonlyassigned application no. 13/024,727 filed Feb. 10, 2011 entitledNON-INVASIVE METHODS AND DEVICES FOR INDUCING EUPHORIA IN A PATIENT ANDTHEIR THERAPEUTIC APPLICATION. The controller with vagus nervestimulator attached may be tuned by preliminarily stimulating thepatient to determine the effect that the stimulation has on the valuesof the measured physiological signals, for given sets of stimulatorparameter values. Such indices will normally fluctuate, so after tuning,the stimulator may then be used to continuously and automaticallystimulate the patient to minimize the error between the fluctuatingphysiological variable values and their setpoints. The inventioncontemplates that such feedback control could involve variation in anyof the stimulator's parameters, including the amplitude of thestimulation signal.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A method of averting the onset of an acute medical event in apatient, comprising: using one or more sensors to detect physiologicaland/or environmental signals within, on, and/or about the patient; usingvalues of said signals to forecast the onset of the acute medical event;positioning a device adjacent to a skin surface of the patient;generating one or more electrical impulses with the device; andtransmitting the electrical impulses to selected nerve fibers in thepatient to treat the acute medical event.
 2. The method of claim 1further comprising generating shaped electrical impulses within thedevice and transmitting them to the patient through a conducting mediumwithin the device.
 3. The method of claim 1 wherein the electricalimpulses are sufficient to avert an acute event, selected from a groupof events comprising asthma attack, epileptic seizure, attack ofmigraine headache, transient ischemic attack or stroke, onset of atrialfibrillation, myocardial infarction, onset of ventricular fibrillationor tachycardia, panic attack, and attack of acute depression.
 4. Themethod of claim 1 wherein the electrical impulses are transmittedtranscutaneously through an outer skin surface of the patient togenerate an electrical impulse at or near the selected nerve fibers. 5.The method of claim 2 wherein the transmitting step is carried out bytranscutaneously passing an electrical current through the outer skinsurface of the patient to a target region within the patient.
 6. Themethod of claim 5 further comprising generating an electrical field ator near the device and shaping the electrical field such that theelectrical field is sufficient to modulate a nerve at the target region;and wherein the electric field is not sufficient to substantiallymodulate a nerve or muscle between the outer skin surface and the targetregion.
 7. The method of claim 6 wherein the electric field is notsufficient to substantially produce movement of a skeletal muscle of thepatient.
 8. The method of claim 2 wherein the transmitting step iscarried out by generating a magnetic field exterior to the patientsufficient to induce an electrical impulse at or near the selected nervewithin the patient.
 9. The method of claim 1 wherein the selected nervefibers are at least approximately 0.5-2 cm below an outer skin surfaceof the patient.
 10. The method of claim 1 wherein the selected nervefibers are associated with a vagus nerve of the patient.
 11. The methodof claim 1 wherein the electrical impulses comprise bursts of pulseswith a frequency of between about 5 to 100 bursts per second (Hz). 12.The method of claim 11 wherein each bursts contains between 1 and 20pulses.
 13. The method of claim 11 wherein the pulses are fullsinusoidal waves.
 14. The method of claim 11 wherein each pulse is about50-1000 microseconds in duration.
 15. The method of claim 1 wherein thephysiological signal monitors one or more of: heart rate or heart ratevariability, ECG or arrhythmia, EEG or sleep state, brain function,respiration, a component of breath, core temperature, hydration, volume,blood pressure, blood flow, blood oxygenation, EMG, patient motion,posture, gait, skin conductance or skin temperature.
 16. The method ofclaim 1 wherein the environmental signal monitors one or more of:formaldehyde, carbon monoxide, carbon dioxide, ozone, a nitrogen oxide,a sulfur oxide, total volatile organic compounds, ammonia, airborneparticles or dust, pollen, mold, animal dander, dust mites, smokeparticulates, ambient temperature, ambient humidity, ambient light, orambient sound.
 17. The method of claim 1 wherein the forecast uses amodel selected from: an autoregressive model, a principal componentmodel, a Kalman filter, a wavelet transform model, a hidden Markovmodel, an artificial neural network, or a support vector machine. 18.The method of claim 1 wherein the forecast uses a black-box or gray-boxmodel.
 19. A device for averting an acute attack in a patientcomprising: a housing having an electrically permeable or conductingcontact surface for contacting an outer skin surface of a patient; anenergy source within the housing configured to generate an electricfield sufficient to transmit an electric current through the outer skinsurface of the patient to a nerve at a target region within the patient;and wherein the electric current is sufficient to avert or at leastpartially ameliorate the acute event, selected from a group of eventscomprising asthma attack, epileptic seizure, attack of migraineheadache, transient ischemic attack or stroke, onset of atrialfibrillation, myocardial infarction, onset of ventricular fibrillationor tachycardia, panic attack, and attack of acute depression.
 20. Thedevice of claim 19 wherein the energy source comprises a signalgenerator and one or more electrodes coupled to the signal generatorwithin the housing.
 21. The device of claim 20 further comprising aconducting medium within the housing between the electrodes and theelectrically permeable contact surface.
 22. The device of claim 19wherein the energy source comprises a battery.
 23. The device of claim20 wherein the signal generator is configured to generate an electricfield comprising bursts of pulses with a frequency of about 5 to about100 bursts per second.
 24. The device of claim 23 wherein the electricfield comprises bursts of between 1 and 20 pulses with each pulse about50-1000 microseconds in duration.
 25. The device of claim 19 wherein theenergy source comprises one or more toroids within the housingconfigured to generate a magnetic field sufficient to induce theelectric field.
 26. The device of claim 25 further comprising aconduction medium within the housing between the toroids and theelectrically permeable contact surface.
 27. The device of claim 19wherein the electric current is sufficient to stimulate a vagus nerve ofthe patient.
 28. The device of claim 19 wherein the housing is ahandheld device configured for contacting a surface of the skin of apatient.
 29. The device of claim 19 wherein the surface of the skin liesover a vagus nerve.